review article sar and computer-aided drug design...

Hindawi Publishing CorporationJournal of Computational MedicineVolume 2013 Article ID 406049 38 pageshttpdxdoiorg1011552013406049

Review ArticleSAR and Computer-Aided Drug Design Approaches inthe Discovery of Peroxisome Proliferator-Activated Receptor 120574Activators A Perspective

Vaibhav A Dixit and Prasad V Bharatam

Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research (NIPER)S A S Nagar Punjab 160062 India

Correspondence should be addressed to Prasad V Bharatam pvbharatamniperacin

Received 28 November 2012 Accepted 28 January 2013

Academic Editor Michele Migliore

Copyright copy 2013 V A Dixit and P V Bharatam This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Activators of PPAR120574 Troglitazone (TGZ) Rosiglitazone (RGZ) and Pioglitazone (PGZ) were introduced for treatment of Type 2diabetes but TGZ and RGZ have been withdrawn from themarket along with other promising leads due cardiovascular side effectsand hepatotoxicity However the continuously improving understanding of the structurefunction of PPAR120574 and its interactionswith potential ligands maintain the importance of PPAR120574 as an antidiabetic target Extensive structure activity relationship (SAR)studies have thus been performed on a variety of structural scaffolds by various research groups Computer-aided drug discovery(CADD) approaches have also played a vital role in the search and optimization of potential lead compoundsThis paper focuses onthese approaches adopted for the discovery of PPAR120574 ligands for the treatment of Type 2 diabetes Key concepts employed duringthe discovery phase classification based on agonistic character applications of various QSAR pharmacophore mapping virtualscreening molecular docking and molecular dynamics studies are highlighted Molecular level analysis of the dynamic nature ofligand-receptor interaction is presented for the future design of ligands with better potency and safety profiles Recently identifiedmechanism of inhibition of phosphorylation of PPAR120574 at SER273 by ligands is reviewed as a new strategy to identify novel drugcandidates

1 Introduction to Diabetes

Diabetes is a metabolic disorder caused mainly by insulinresistance and obesity It is now recognized as a major healthproblem worldwide and affects adults of working age indeveloping countries WHO estimates of global prevalenceare expected to increase from 171 million in 2000 to 366million in 2030 and 217 (ie sim8 crores) of these willbe Indians [1] The chronic nature of this disease leadsto metabolic complications like kidney failure and cardiacproblems Early diagnosis and controlled diet combined withphysical exercise of just thirty minutes have been shown toprovide control in the progression of the disease

Increasing technological advancements and decreasingproportion of physical activities in routine life are promotingsedentary lifestyle Thus pharmacological intervention may

remain the only choice in certain group of subjects Inaddition lack of proper treatment and delayed diagnosis arethe twomajor reasons for the increased economic burden andprevalence of diabetes in the developing countries

Diabetes is generally classified into three classes (1) Type1mdashcaused by complete lack of insulin production (2) Type2mdashdue to insulin resistance and ineffective downstream sig-naling in the cell and (3) gestational diabetesmdashaffects 4 ofall pregnantwomen and is rarely fatal Almost 90of all casesof diabetes are Type 2 class All these facts and figures haveforced most of the governments and scientists world over tolook for effective therapies resulting in a mammoth of effortsin the discovery and development of novel drug candidates

These efforts have been based on a variety of drugtargets and have led to introduction of a few drugs in themarketThese drugs and their targets are brieflymentioned in

2 Journal of Computational Medicine

Table 1 Current treatment against Type 2 diabetes mellituslowast

Compounds Examples Mechanism Adverse effects

Secretagogues (sulfonylureasnonsulfonylureas) Glibenclamide meglitinide Increase of insulin secretion

Hypoglycaemiahyperinsulinaemia weight gainand vomiting

Biguanides Metformin Decrease of hepaticglucose output

Diarrhoea vomiting and lacticacidosis

120572-Glucosidase inhibitors Acarbose miglitol voglibose Inhibition of carbohydrateabsorption

Flatulence diarrhoea andabdominal pain

GLP1 GIP and DPP IV Exenatide LAF-237Liraglutide CJ-1131

Incretin effect improvement of120573-cell function Vomiting nausea

Thiazolidinediones Pioglitazone and Rosiglitazone PPAR120574 activation Weight gain oedemalowastModified from [2]

Section 2 The focus of this paper is to highlight the majorSAR and CADD studies performed on PPAR120574 Readersinterested in other targets are suggested to consult some of theexcellent recent and older reviews published on these topics[3ndash5] A brief literature search shows that a large amount ofwork has been done for the identification and testing of novelscaffolds for antidiabetic drug discovery in the PPAR arena Areview on PPAR120574 ligands was published with focus on dualpan and SPPARMs based strategy in 2008 [6] As discussedin the Section 32 a large number of crystal structure havebeen published for PPAR120574-ligand complexes but a thoroughunderstanding about the links between receptor-ligand inter-actions and antidiabetic benefits is far from completeThus anexpert perspective and overall assessment of these efforts areurgently required to give proper direction to these attempts

This paper begins with a brief introduction to currenttherapies for Type 2 diabetes followed by PPAR120574 localizationstructure and its ligands (natural and synthetic) This isfollowed by a brief classification of the ligands based on theiragonistic character Next in an attempt to fill the gaps inthe understanding of structure and function of PPAR120574 andits ligands this review is divided into sections on (i) SARstudies performed in the past twelve years An attempt hasbeenmade to present these studies in the chronological orderbut some exceptions are allowed to maintain connectivitybetween selected studies Majority of these studies involvedclassical medicinal chemistry approach to build SAR thatis to modify the substituents on a structural scaffold usingmostly biochemical intuition till the desired activityaffinityis observed (ii) Rational drug design approaches usingcomputational methods are then discussed In this sectionalso a chronological order has been followed with someexceptions and QSAR (2D 3D and higher-dimensionalmethods) pharmacophoremappingmolecular docking andstructure-based ligand based and de novo drug designapproaches employed are discussed

Despite the large number of SAR and CADD studiesreported on PPAR120574 agonists none of themolecules has madeit to the clinic after the introduction of TZDs Incompleteunderstanding of the dynamical nature of PPAR120574-ligandinteractions and translation of these interactions into phys-iological response could be one of the major reasons forthis failure Molecular dynamics simulation studies coupled

with other experimental techniques that have been utilizedby some groups to bridge these gaps are discussed brieflyRole of recently identified implications of phosphorylation ofPPAR120574 residues and resulting nonagonisticpartial agonisticcharacter of novel ligands is highlighted in the last section

2 Current Treatment Options forType 2 Diabetes

The cause of insulin resistance has been traced to defectsin insulin receptor (IR) function IR-signal transductionglucose transport and phosphorylation glycogen synthesisglucose oxidation and dysregulation of fatty acidmetabolism[7] Consequently these defects are targets of current phar-macological treatments as well as potential sites for newtherapies

Figure 1 shows the structures of currently marketed anda few withdrawn drugs which form the existing armoragainst Type 2 diabetes (see also Table 1) The biguanideslike metformin reduce the hepatic glucose production andalso enhance muscle insulin sensitivity Acarbose decreasesgastrointestinal absorption of carbohydrates by inhibiting 120572-glucosidase The sulfonylureas bind to specific receptors onthe 120573 cells of pancreas resulting in inhibition of K+ channelsleading to depolarization of cell membrane followed byexocytosis of insulin The dipeptidyl peptidase IV inhibitorsexert their antidiabetic effects by inhibiting the metabolismof glucagon-like peptide-1 (GLP-1) GLP-1 mediates its effectsthrough transmembrane GPC receptors leading to increasedinsulin secretion in response to feeding It has also beenshown to enhance the differentiation survival and matura-tion of the 120573 cells [8] This has encouraged the developmentof GLP-1 analogs also known as incretin mimetics likeexenatide a 39-amino acid peptide with glucoregulatoryproperties

Most of the above-mentioned drugmolecules act as director indirect insulin secretagogues of moderate to low poten-ciesThemajor cause of Type 2 diabetes a generalized insulinresistance in the body is actually not addressed by theselines of therapyThiazolidinediones (TZD) were identified in1995 to exert their antidiabetic actions by binding to PPAR120574with high affinity [9] This is the only class of molecules thatdecrease generalized insulin resistance in tissues like muscle

Journal of Computational Medicine 3

N

N

N

O O

N N

NN

NO

ON

N

N

N

NO

H

H

N

N

O

VildagliptinApproved in EU

AlogliptinNDA submitted

Linagliptinphase III

Saxagliptinphase III

BMS

O

F

F

FN N

N N

F

F F

SitagliptinApproved by US FDA

Dipeptidyl peptidase IV inhibitors

Sulfonylureas

OOS

O

O HN

HN

HN

HN

HN

HN

O

ClGlibenclamide

SO

ONH

NH

NH

NH

NH

NH

NH

O

Tolbutamide

N

OOS

O

O

O

Glimepiride

NN

O

SO

O

O

Glipizide

Metformin

N

Phenformin

Biguanides

Withdrawn

Thiazolidinediones

S

NHO

OO

N

N

Rosiglitazone (RGZ)

S

NHO

OON

Pioglitazone (PGZ)

S

NHO

OOOHO

Troglitazone (TGZ)Withdrawn

OO

O

OH

OH

OHOH

HO

HO

HO

HO

HO

OO

NH

OH

OHOH

OHOH

HO

Acarbose

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-

GLP-1 Analog

Amylin Pharmaceuticals and Eli LillyExenatide

N N

H2N

H2N

H2N H2N

NH2

NH2

NH2

NH

NHNH2

NH2

120572-glucosidase inhibitor

Figure 1 Currently marketed and a few withdrawn antidiabetic drugs


and adipose Rosiglitazone (RGZ Avandia) and Pioglitazone(PGZ Actos) are the twomost widely used drugs in the treat-ment of diabetes Troglitazone (TGZ Rezulin) was also in themarket since 1997 until hepatotoxicity forced its withdrawalin 2000 [10 11] TZDs are potent agonists of the peroxisomeproliferator-activated receptor 120574 (PPAR120574) a ligand-activatedtranscription factor thought to be a master regulator ofadipocyte differentiation andmultiple adipocyte genes Acyl-CoA synthaseoxidase Apolipoprotein AC CPTI (carnitinepalmitoyl transferase I) CYP4A1P450 IV family lipopro-tein lipase mitochondrial 3-hydroxy-3-methylglutaryl-CoAsynthase phosphoenolpyruvate carboxykinase (PEPCK)uncoupling protein 1 and so forth are a few target proteinsof PPAR120574 activation indicating its important role in carbo-hydrate and lipid metabolism In addition to this there is acomplex feedbackmechanismbetween the adipose tissue andinsulin sensitivity Adiponectin a peptide hormone secretedby the adipocytes during differentiation has been shown todecrease insulin resistance [12] Although TZDs have beenobserved to increase the expression of adiponectin it is notclear whether this is a direct result of PPAR activation or iscaused by secondary effects

3 Peroxisome Proliferator-ActivatedReceptor 120574 (PPAR120574)

31 PPAR Location and Organization Peroxisome prolifer-ator-activated receptors (PPARs) belong to a super familyof nuclear receptors Phylogenetic studies suggest that theancestral genes associated with PPAR might have appearedmore than 500 million years ago during the eukaryotic evo-lution [13] They are present in the cytoplasm as monomersbut upon activation by the ligand they heterodimerize withretinoid X receptor 120572 (RXR120572) and enter the nucleus toregulate transcription of a wide variety of receptors andenzymesThree isotypes (PPAR120572 120574 and120573120575) have been iden-tified and the human-PPAR120574 (hPPAR120574) has been located onchromosome 3 at position 3p25 close to retinoid X receptor 120573(RXR120573) and Thyroid hormone receptor 120573 (TR120573) [14] whilePPAR120572 and PPAR120573120575 have been assigned to chromosomes22 and 6 respectively For hPPAR120574 three isoforms have beenidentified (PPAR1205741 PPAR1205742 and PPAR1205743) based on thedifferential use of three promoters and alternative splicing ofthe three 51015840-exons A1 A2 and B1 [15] Amino acid sequencesand various regions in the receptor are depicted in Figure 2

In PPARs two main functional domains have beenidentified namely (i) DNA-binding domain (DBD) and (ii)ligand-binding domain (LBD) The DNA-binding domain isthe hallmark of nuclear receptor superfamily and is formedby highly conserved two zinc finger-like motifs folded in atertiary structure that can recognize DNA target sequencesof six nucleotides It is specific for direct repeat of twocore recognitionmotifs AGGTCA spaced by one nucleotidehence called DR1 These nucleotide sequences are alsoknown as PPAR response elements (PPREs) For CYP4A6an extended consensus sequence for PPRE has been identi-fied (51015840-AACTAGGNCAAAGGTCA-31015840) These distinguish-ing features of PPRE contribute to PPAR-RXR heterodimerspecificity and differential regulation of transcription

32 PPAR120574 3D Structure PPAR120574 consists of 13 120572 helices andfour 120573-sheets The overall structure is very similar to othernuclear receptors from helix H-3 to C terminus and has oneextra small helixH-21015840 HelicesH-3 H-7 H-10 andH-12 alongwith the 120573-sheets arranged in antiparallel orientation con-stitute a large-ligand binding pocket of this nuclear receptor(Figure 3) [16] In the crystal structure with PDB code 2PRGthe RGZmolecule is found to straddle helix H-3 and interactswith four residues SER289 HIS323 HIS449 and TYR473stronglyThis set of interactions is generally considered as themolecular recognition interaction and any ligand showingthis set of interactions is considered as an effective agonist(though many exceptions are found) RGZ takes a U shapein this Y-shaped active site (Figure 3) Table 2 shows activesite shapes and volumes of some representative cocrystalstructures of important ligands with PPAR120574 A search in thePDB database retrieved a large number of crystal structures(112) for PPAR120574 (13) for PPAR120572 and (22) for PPAR120573120575(search performed on 23112012) PDB codes resolution ofthe crystal structures and citation are shown in Table 3 Inmost of the crystal structures agonists are bound with theLBD of PPAR120574 A closer inspection and analysis of the crystalstructures reveal that the active site shape and importantinteractions in the active site are similar for most of theagonists The active site consists of Y-shaped binding pocketin which the acidic head groups of the ligands interact withthe H-12 helix by forming hydrogen-bonding interactionswith HIS323 HIS449 and TYR473 amino acid residues

Figure 4 shows the general pharmacophoric featurespresent in PPAR120574 agonists as exemplified for RGZ InFigure 5(a) RGZ is seen to bind in a U shape in the Y-shapedactive site by forming strong hydrogen-bonding interactionswith mainly polar residues (PDB code 2PRG) The othertwo arms of the active site are relatively nonpolar consistingof mainly hydrophobic residues Induced fit conformationalchanges in the active site shape have also been seen toaccommodate larger ligands like Farglitazar leading to theformation of additional subpocket in the active site givingit an almost 120583 shape (PDB code 1FM9 see Figure 5(e))Partial agonists can bind near the H-12 helix (eg clofibricacid analogue Figure 5(f)) or near the 120573-sheet region (egBVT13 Figure 5(g)) Endogenous ligand 15d-PGJ2 takes analmost Y shape in the active site of PPAR120574 (PDB code2ZVT 2ZK1 and 2ZK2) thus highlighting the importanceof the interactions in all the three arms of the receptor forphysiological response

Three 3D structures of DNA-RXR120572-PPAR120574 tertiary com-plex were reported by Chandra et al in 2008 [19] The DBDand LBD of PPAR120574 have overall topology similar to thosereported in other monomer and dimer crystal structuresof PPAR120574 Structures of terminal helices known to bind tothe DNA were clearly seen in these heterodimer structuresAnalysis of LBD of PPAR120574 in this heterodimer shows thatit interacts with the PPRE more closely than RXR120572 PPAR120574resides upstream of RXR120572 giving a polar arrangement ofthese nuclear receptors on the PPRE Helices H-7 H-9 andH-10 of each receptor form DNA-dependent contacts and


1 101 166 244 468AB C D EF

1 72 137 215AB C D EF

441

1 110 175 251AB C D EF

477

DNA-binding domain

Ligand-binding domain

Ligand-independentactivation domain

AF-1


AF-2

hPPAR120572

hPPAR120573

hPPAR1205741

Figure 2 Functional domains of the PPAR family are represented schematically Ligand-dependent activation domain (AF-1) consists ofdomains AB DNA-binding domain (C) and domain D Ligand-dependent activation function (AF-2) consists of domains EF and formsthe ligand binding site with importantmolecular recognition interactions in the receptor hPPAR1205741 is the largest isoform (477AAs) (Modifiedfrom [15])

Figure 3 Rosiglitazone (RGZ) takes U shape in the Y-shaped activesite of PPAR120574 (PDB code 2PRG) The TZD ring forms hydrogen-bonding interactions with HIS323 HIS449 and TYR473 in theactive site Figure is generated using LigSite [17] and PyMol [18]

Table 2 Active site shape and volume for PPAR120574 agonists (seeFigure 5)

PDB Ligand Active siteshape

Active sitevolume

2PRG RGZ (A) Y 1703 A3

2PRG PGZ (B) Y 1703 A3

2PRG Barbituric acid analogue (C) Y 1703 A3

2Q59 MRL20 (D) L 1407 A3

1FM9 Farglitazar (E) 120583 1815 A3

3CDP Clofibric acid analogue (F) 120583 1598 A3

2Q5P MRL24 (G) L 1218 A3

2Q6S BVT13 (H) L 1568 A3

lead to DBD (PPAR120574)-DBD (RXR120572) interaction of approxi-mately 2160 A2 solvent accessible surface area (Figure 6)Thestructure shows that PPAR120574 LBD interacts with DBD and

LBD of the RXR120572 and DNA Three well understood ligandsRosiglitazone (RGZ) GW9662 and BVT13 gave rise to a ldquoY-shapedrdquo pocket This suggests that Y-shaped ligands may fitbetter in the active site with higher affinity

33 PPAR120574 Ligands

331 Natural (Endogenous) Ligands Polyunsaturated fattyacids like linolenic acid eicosapentaenoic acid 9-hydroxy-1012-octadecadienoic acid (9-HODE) 13-hydroxy-911-octadecadienoic acid (13-HODE) and 15-deoxy-Δ1214-prostaglandin J2 (15d-PGJ2) are important endogenousligands of PPAR120574 (Figure 7) They bind with lower (119870D sim2ndash50 120583M) affinity to PPAR120574 Through interaction withthese fatty acids PPAR120574 is thought to monitor the lipidconcentrations and maintain homeostasis in the cytoplasmThe oxidized forms of prostaglandins induce adipocytedifferentiation at low micromolar levels

332 Synthetic Ligands Since the discovery of Ciglitazone(CGZ) as effective insulin-sensitizing agent by Shoda et al[20] many synthetic ligands of PPAR120574 have been identifiedThey have shown a wide variety of activation profiles basedon receptor-binding affinity and transactivation assaysThusbased on the dose-response curves they cac acid analoguesBVT13 andMRL24 and so forth (iii) dual PPAR120574120572 agonists(iv) selective PPAR120574 modulators (SPPARMs) and the leaststudied (v) antagonists A recent review has reported clas-sification based on the agonistic activity as well as chemicalgroup [21] The classification based on agonistic activity ismore useful for understanding the activity profiles and result-ing antidiabetic effects and hence is given in the following

Full Agonists Full agonists like RGZ PGZ TGZ and MRL20lead to complete activation of PPAR120574 as shown by dose-response curves generated using transactivation assays


Table3Listof

PPAR120574

crystalstructuresd

epositedin

theP

DBdatabank

asof

2311

2012Re

solutio

nandprim

arycitatio

nfore

achstructurea

realso

given

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

1FM9

210

PPAR120574

2000

2-(2-BEN

ZOYL

-PHEN

YLAMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[22]

1GWX

250

PPAR120575

1999

2-(4-(3-[1-[2-(2-CH

LORO

-6-FLU

ORO

-PHEN

YL)-ET

HYL

]-3-(23-D

ICHLO

RO-

PHEN

YL)-URE

IDO]-PR

OPY

L)-PHEN

OXY

)-2-MET

HYL

-PRO

PIONIC

ACID

[23]

1I7G

220

PPAR120572

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1I7I

235

PPAR120574

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1K7L

250

PPAR120572

2001

2-(1-MET

HYL

-3-O

XO-3-PHEN

YL-PRO

PYLA

MIN

O)-3-(4-[2-(5-M

ETHYL

-2-

PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[25]

1KKQ

300

PPAR120572

2002

N-((2S)-2-(((1Z)-1-M

ETHYL

-3-O

XO-3-[4-(TRIFL

UORO

MET

HYL

)PH

ENYL

]PRO

P-1-E

NYL

)AMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-

YL)ETH

OXY

]PHEN

YL)PRO

PYL)PR

OPA

NAMID

E[26]

1KNU

250

PPAR120574

2002

(S)-3-(4-(2-CA

RBAZO

L-9-YL

-ETH

OXY

)-PH

ENYL

)-2-ET

HOXY

-PRO

PIONIC

ACID

[27]

1NYX

265

PPAR120574

2003

(2S)-2-ETH

OXY

-3-(4-[2-(10H-PHEN

OXAZIN-10-

YL)ETH

OXY

]PHEN

YL)PRO

PANOIC

ACID

[28]

1PRG

220

PPAR120574

1998

[16]

1WM0

290

PPAR120574

2004

2-[(24-DICHLO

ROBE

NZO

YL)A

MIN

O]-5-(PYR

IMID

IN-2-YLO

XY)BEN

ZOIC

ACID

[29]

1Y0S

265

PPAR120575

2000

(2S)-2-(4-[2-(3-[24-D

IFLU

ORO

PHEN

YL]-1-H

EPTY

LURE

IDO)ETH

YL]PHEN

OXY

)-2-MET

HYL

BUTY

RICAC

ID[30]

1ZEO

250

PPAR120574

2005

(2S)-(4-ISOPR

OPY

LPHEN

YL)[(2-M

ETHYL

-3-O

XO-57-DIPRO

PYL-23-DIH

YDRO

-12

-BEN

ZISO

XAZO

L-6-YL

)OXY

]ACE

TATE

[31]

1ZGY

180

PPAR120574

2005

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[32]

2ATH

228

PPAR120574

2005

2-(5-[3-(7-PRO

PYL-3-TR

IFLU

ORO

MET

HYL

BENZO

[D]ISO

XAZO

L-6-

YLOXY

)PRO

POXY

]INDOL-1-Y

L)ET

HANOIC

ACID

[33]

2AWH

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]

2B50

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2BAW

230

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[35]

2ENV

Solutio

nstructure

PPAR120575

Tobe

publish

edZINCIO

N

2F4B

207

PPAR120574

2006

(5-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

POXY

)-1H

-INDOL-1-

YL)A

CETICAC

ID[36]

2FVJ

199

PPAR120574

2006

GLY

CERO

L[37]

2G0G

254

PPAR120574

2006

3-FL

UORO

-N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-

YL]BEN

ZENES

ULF

ONAMID

E[38]

2G0H

230

PPAR120574

2006

N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-YL

]-35-

BIS(TR

IFLU

ORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[38]

2GTK

210

PPAR120574

2006

(2S)-3-(1-([2-(2-CH

LORO

PHEN

YL)-5-MET

HYL

-13-O

XAZO

L-4-YL

]MET

HYL

)-1H

-IN

DOL-5-YL

)-2-ET

HOXY

PROPA

NOIC

ACID

[39]

2GWX

230

PPAR120575

1999

[23]

2HFP

200

PPAR120574

2006

3-(4-M

ETHOXY

PHEN

YL)-N-(PH

ENYL

SULF

ONYL

)-1-[3-

(TRIFL

UORO

MET

HYL

)BEN

ZYL]-1H-INDOLE

-2-C

ARB

OXAMID

E[40]

2HWQ

197

PPAR120574

2006

[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-5-

YL)O

XY]A

CETICAC

ID[41]

2HWR

234

PPAR120574

2006

2-[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-4-

YL)O

XY]-2-MET

HYL

PROPA

NOIC

ACID

[41]

2I4J

210

PPAR120574

2007

(2R)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4P

210

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4Z

225

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2J14

280

PPAR120575

2006

(3-(4-[2-(24-DICHLO

RO-PHEN

OXY

)-ET

HYL

CARB

AMOYL

]-5-PH

ENYL

-ISOXAZO

L-3-YL

)-PH

ENYL

)-ACE

TICAC

ID[43]

2NPA

230

PPAR120572

2007

(2R3E

)-2-(4-[(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)MET

HOXY

]BEN

ZYL)-3-

(PRO

POXY

IMIN

O)BUTA

NOIC

ACID

[44]

2OM9

280

PPAR120574

2007

(6AR10AR)-3-(11-D

IMET

HYL

HEP

TYL)-1-HYD

ROXY

-66-D

IMET

HYL

-6A71010

A-TE

TRAHYD

RO-6H-BEN

ZO[C

]CHRO

MEN

E-9-CA

RBOXY

LICAC

ID[45]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2P4Y

225

PPAR120574

2008

(2R)-2-(4-CH

LORO

-3-([3-(6-MET

HOXY

-12-BEN

ZISO

XAZO

L-3-YL

)-2-MET

HYL

-6-

(TRIFL

UORO

MET

HOXY

)-1H

-INDOL-1-

YL]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[46]

2P54

179

PPAR120572

2007

2-MET

HYL

-2-(4-([((4-MET

HYL

-2-[4-(TRIFL

UORO

MET

HYL

)PHEN

YL]-13

-TH

IAZO

L-5-YL

)CARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[47]

2POB

230

PPAR120574

2007

N-[(2S)-2-[(2-BEN

ZOYL

PHEN

YL)A

MIN

O]-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-

OXAZO

L-4-YL

)ETH

OXY

]PHEN

YL)PRO

PYL]AC

ETAMID

E[48]

2PRG

230

PPAR120574

1998

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[16]

2Q59

220

PPAR120574

2007

(2S)-2-(2-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5G

270

PPAR120575

2007

[(7-([2-(3-M

ORP

HOLIN-4-YLP

ROP-1-Y

N-1-

YL)-6-([4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]ETH

YNYL

)PYR

IDIN

-4-YL]TH

IO)-23-DIH

YDRO

-1H

-INDEN

-4-YL)OXY

]ACE

TICAC

ID[50]

2Q5P

230

PPAR120574

2007

(2S)-2-(3-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5S

205

PPAR120574

2007

5-CH

LORO

-1-(4-C

HLO

ROBE

NZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q61

220

PPAR120574

2007

1-BEN

ZYL-5-CH

LORO

-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-C

ARB

OXY

LICAC

ID[49]

2Q6R

241

PPAR120574

2007

5-CH

LORO

-1-(3-M

ETHOXY

BENZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q6S

240

PPAR120574

2007

[49]

2Q8S

230

PPAR120574

2008

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(1H-

PYRR

OL-1-Y

L)PR

OPA

NOIC

ACID

[51]

2QMV

Solutio

nNMR

PPAR120574

Tobe

publish

ed

2REW

235

PPAR120572

Tobe

publish

edNN-BIS(3-D

-GLU

CONAMID

OPR

OPY

L)DEO

XYCH

OLA

MID

E

2VSR

205

PPAR120574

2008

(9S10E12Z)-9-H

YDRO

XYOCT

ADEC

A-1012

-DIENOIC

ACID

[52]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker

Figure 4 Pharmacophoric features in a PPAR120574 agonist Rosiglitazone (RGZ)

(a) (b) (c) (d)

(e) (f) (g) (h)

Figure 5 Active site shape and volumes occupied by PPAR120574 ligands First row shows PPAR120574 full agonists RGZ (a) PGZ (b) Barbituric acidderivative (c) andmoderate agonist MRL20 (d) Second row shows PPAR120574 partial agonists Farglitazar (e) clofibric acid analogue (f) BVT13(g) andMRL24 (h) Docked poses were used for active site analysis for PGZ and barbituric acid analogue Calculations were performed usingPocketFinder which is a modification of LigSite [17]

RXR120572cis-Retinoic

acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)

Figure 6 PPAR120574-RXR120572-DNA cocomplex crystal structureobtained with RGZ and cis-Retinoic acid bound in the active site(PDB code 3DZY) Proximity of PPAR120574 LBD with RXR120572 LBD andPPRE (DNA) is clear Interaction of C-terminal helices in the majorgrove of the DNA and Zn finger motif provides clues for gradedactivation of different genes by different ligands This figure hasbeen generated using PyMol [18]

While compounds like endogenous fatty acids and theirnitrated derivatives BVT13 Farglitazar MRL24 andnTZDpa do not lead to complete activation of the receptorand thus can be classified as partial agonists Any ligandshowing more than 60 of the transactivational activityshown by RGZ is classified as a full agonist Ligands withtransactivational activity near 60 are moderate agonistsbut sometimes are referred as full agonists (eg MRL20)Partial agonists generally have less than 50 transactivationalactivity compared to RGZ [24 49 94] Although this is areasonably correct definition any two ligands should becompared only when similar or identical transactivationalassays have been utilized in obtaining the dose-responsecurves This is due to the dependence of the observedtransactivational activity on the many factors like cell type(adipose muscle kidney or liver used) presenceabsenceof coactivatorscorepressors PPRE used and so forth[95] Figure 8 shows 2D structures of some full agonistsCrystallographic [16 19] and mutation studies [46] haveestablished the role of H-12 helix and TYR473 in the activityof full agonists

The tyrosine amino acid residue (TYR473) present in theH-12 helix of AF-2 function forms strong hydrogen-bondinginteractions with acidic head groups of full agonists as seenin Figure 3 This pocket of the active site consists of mostlypolar residues (SER289 HIS323 HIS449 and TYR473) thus


Linolenic acid (1)

O OH

58111417-Icosapentaenoic acid(eicosapentaenoic acid2)

9-Hydroxy-1012-octadecadienoic acid(9-HODE 3)

O

OH

OH

OH

OHHO


O

(Z)-7-[(1S5E)-5-[(E)-oct-2-enylidene]-4-oxocyclopent-2-en-1-yl] hept-5-enoic acid

OO

OOH

15-deoxy-Δ1214-prostaglandin J2 (15d-PGJ2 5)

Figure 7 PPAR120574 endogenous ligands are mostly polyunsaturated fatty acids and their oxidized derivatives

S

O

O

ON

Pioglitazone (PGZ) (7)

SNH

O

O

OOHO

Troglitazone (TGZ) (8)

SNH

O

O

O

Ciglitazone (CGZ) (9)

O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO

Barbituric acid analogue (11)

SNH NH

O

O

ONN

Rosiglitazone (RGZ) (6)

Figure 8 PPAR120574 full agonists have polar acidic head groups essential for interaction with the TYR473 of H-12 helix


interactions of full agonists with the receptor are mostlyelectrostatic in nature [96 97]

Such interactions lead to significant stabilization in thefluctuations of the H-12 helix thus stabilizing the activeconformation of the receptor promoting its interaction withthe coactivators and RXR120572 leading to gene transcriptionThus the full agonists have polar acidic head groups anda hydrophobic tail separated by an aromatic or aliphaticlinker These three fragments constitute the pharamcophoreessential for PPAR120574 agonistic activity (Figure 4) Endogenousligands also have structures satisfying these pharmacophoriccriteria

Partial Agonists Bruning et al suggested that partial agonists(see Figure 9) in contrast to the full agonists interact withthe receptor with mostly hydrophobic interactions leadingto PPAR activation that is H-12 helix independent [49]This is evident from their radio-ligand and transactivational-binding assays Farglitazar is known to interact with mostlyhydrophobic interaction in the active site and has largerbinding affinity due to the presence of extra substituent(benzophenone) that interacts in the additional subpocketnear the H-12 helix

Balaglitazone (BGZ 12) a partial agonist discovered byHenriksen et al showed lesser hemodynamic effects of fluidretention and weight gain compared to PGZ in a Phase IIIclinical trial [98] PAT5A (13) a molecule with exocyclicdouble bond in the TZD ring is a partial agonist Treatmentof PAT5A in rodents with Type 2 diabetes resulted in dose-dependent reduction in plasma glucose levels similar to RGZalong with reduced weight gain [99] The partial agonisticcharacter of BGZ and PAT5A points to the fact that agonisticcharacter is not dependent on the groups present in ligandsbut is a function of the dynamical behavior of the H-12helix when the ligand is bound Thus understanding thedynamical behavior of the AF-2 function in PPAR120574 is vitalfor future drug discovery efforts to find ligands with betterpharmacological and safety profiles Other partial agonists sofar discovered generally either bind near the120573-sheet region orhave veryweak interactionswith theH-12 helix [21 49]Thesedifferences in the interaction features lead to recruitmentof different coactivators and thus different gene expressionpatterns in comparison to the full agonists For example TZDclass of compounds showed an increase in the expressionof chemokinemonocyte Chemoattractant protein-1 (MCP-1)whereas 15d-PGJ2 had little effect in a model of experimentalglomerulonephritis (GN) in rats TZD class of compoundsalso showed augmented activator protein-1 (AP-1) bindingbut had little effect on NF-120581B while the 15d-PGJ2 showeddecrease in NF-120581B without affecting AP-1 levels [95]

Dual PPAR120574120572 Agonists PPAR120574 and PPAR120572 show comple-mentary effects of insulin sensitization in the adipocytesmuscles and correction of atherogenic dyslipidemia Thus adual agonist combining the beneficial effects of both full andpartial agonists while avoiding the side effects of weight gainhas been sought by various research groups (see Figure 10) [621 100ndash103] Aleglitazar novel120572-alkoxy-120573-arylpropionic acidderivative derived fromSAR studies [69] has shownbalanced

effects on the glucose and lipidmetabolism in primatemodelsof metabolic syndrome [104] Acidic head group of Alegli-tazar forms important hydrogen-bonding interactions withH-12 helix in both PPAR120574 (HIS323 HIS449 and TYR473)and PPAR120572 (SER280 TYR314 and HIS440) It is currentlyin Phase III clinical trials (January 2012 NCT01042769a study with Aleglitazar in patients with a recent acutecoronary syndrome and type 2 diabetes mellitus) Aryloxy-120572-methylhydrocinnamic acid derivative LYS10929 with athiophene tail showed insulin-sensitizing effects decreasedhyperglycemia and improved overall lipid profiles [103]Tesaglitazar an 120572-alkoxy-propionic acid derivative showedpromise as a dual agonist [105] butwas laterwithdrawn fromaphase III clinical study due to increased serum ceratinine anddecrease in glomerular filtration rates [106] Although dualagonists demonstrated beneficial impact over selective PPARagonists by improving both lipid and glucose homeostasessafety has been a critical issue and has led to the discontinua-tion of their development because of adverse toxicity profiles[101] Molecules like Tesaglitazar and Ragaglitazar have beensuspended in Phase III and Muraglitazar has failed to get acontinued FDA approval

Selective PPAR120574 Modulators (SPPARMs) Selective PPAR120574modulators (SPPARMs) are defined as ligands which induceagonistic or antagonistic responses depending on the cellularcontext and lead to expression of specific target genes [107]A SPPARM is different from partial agonist because the dose-response relationships for various activities are uncoupledfrom each other This can be understood as resulting fromtissueorgan specific responses which are not directly relatedto each other [21 107] Efforts in this direction resultedin the identification of Fmoc-L-leucine as SPPARM withmost characteristics like a partial agonist [108] Figure 11shows 2D structures of selected SPPARMs Metaglidasen anenantiomer of halofenate was found efficient at reducingglucose levels and having beneficial effects on lipid profilesThis drug candidate a prodrug is hydrolyzed by nonselectiveesterases in the plasma and converted to active metaboliteDue to uricosuric properties this molecule was repositionedin the treatment of gout by Metabolex Inc [109] FK-614was found to be a structurally novel SPPARM with insulinsensitizing activities But due to adipocyte hypertrophy itsfurther development was halted [110] Telmisartan usedin the treatment of hypertension was rediscovered as aSPPARM which binds to PPAR120574 in a conformation differentfrom TZDs [111] Insulin-sensitizing effects of Telmisartanfueled its development as a combination therapy in patientswith diabetes and cardiovascular complications [112] It iscurrently used in the trade name MICARDIS (80mg) fortreating hypertension

Antagonists of PPAR120574 Both covalent and noncovalent antag-onists of PPAR120574 have been identified (see Figure 12) Antag-onists of PPAR120574 have similar insulin-sensitizing activitiesbut further studies are required to confirm their clinicalapplications Compound GW9962 forms a covalent bondwith the cysteine located on helix H-3 It has shown potentantagonistic activity against PPAR120574 in cell-based assays


SNH

O

O

ON

N

O

Balaglitazone (BGZ) (12)

SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3

Figure 9 2D structures of some representative PPAR120574 partial agonists which interact with PPAR mostly by hydrophobic interactions andalso have vital pharmacophoric features of PPAR agonists (Figure 4)

O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)

Figure 10 PPAR120572120574 dual and partial agonists


O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)

Figure 11 Selective PPAR120574modulators (SPPARMs)

OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus

Figure 12 PPAR120574 antagonists

[113] Polycarbonate-based diglycidyl ether (BADGE) is anantagonist with micromolar potency [114]

4 Structure Activity Relationship (SAR)Studies for PPAR120574 Ligands

With the discovery of TZDs as the potent synthetic agonistsfatty acids and their derivatives as natural ligands of PPAR120574structure activity relationship (SAR) studies were performedby many groups to understand the nature of interactionsbetween the PPAR120574 and its ligands These important SARstudies are discussed briefly in this section

SAR between PPAR120574 binding affinity and antihyper-glycemic effects was reported first time by Willson et alin 1996 [115] In vitro PPAR120574 agonistic activity correlatedaccurately with the in vivo ability of the molecules to causeantihyperglycemic effect Difference in the in vivo activityprofiles of compounds belonging to same chemical classhaving similar pharmacokinetic profiles would have mostlikely arisen from their differences in pharmacodynamics andthus form the intrinsic potency of the moleculesThus resultsfrom this and similar in vitro analysis could logically be usedto screen large libraries of molecules with confidence Thisin vitro SAR study also established the correlation betweenthe antidiabetic effect of TZD class of compounds and PPAR120574binding affinity

Reddy et al reported benzyloxy derivatives of TGZto have better euglycemic and hypolipidemic activity (seeFigure 13) [116] Introduction of ethanolamine linker andbenzyl protection at the hydroxyl group of TGZ resulted incompounds with better in vivo glucose lowering effect indbdb mice and Wistar rats In vivo analysis showed that theunsaturated analogues of TGZ are more effective in loweringthe glucose levels Transactivation assays on the other handshowed that the saturated TGZ derivatives lead to greateractivation of PPAR120574 Such contrasting findings in the invitro and in vivo data were attributed to the differences inpharmacokinetic profiles and use of different salt forms ofthe individual drug candidates TGZ showed toxic effectsin some patients but mechanisms of toxicity were notcompletely understood at that time [117] But involvement ofthe hydroxyl group from the metabolic profile was becomingclear and these lead Reddy et al to design of compounds withhydroxyl group protected by benzyl groups (29) [118] In asubsequent paper Reddy et al reported the modification of aPPAR120572 selective agent leading to the synthesis of PPAR120572120574dual agonist DRF2725 (31) [119] The (-)-isomer of thiscompound was found to be potent in transactivation assaysand showed better antidiabetic and hypolipidemic activityprofile in vivo

Brooks et al reported the synthesis and dual agonisticactivity of an oxazole containing phenoxypropionic acidderivative [120] Substitution of methyl groups at 120572 positionwas found to be necessary for activity The biphenyl substi-tution also increased dual activation profile and gave verypotent compound (32) as a dual PPAR120572120574 agonist

Racemization in the TZD class of compounds has beenwell established by both experimental [121] and theoreticalstudies [122] Bharatam and Khanna performed theoreticalstudies and proposed the importance of S-oxidation in therapid racemization of TZD class of drugs [122] Thus due tothis racemization administration of a pure enantiomer wasnot considered for this class of drugs Haigh et al studied


O

BnO

NO NHS

O

OO-benzyl substituted TGZ derivative (29)

N

ON O

HOOC

N

O

O HN

O

O

O OH

O

A oxazole phenylpropionic acid dervivatives (dual agonist 32)

OCH2CH3

HOOC OCH2CH3

Dual PPAR120572120574 ligand DRF2725 (31)

A PPAR120572 selective ligand (30)

Figure 13 Benzyl protected TGZ derivatives oxazole containing phenoxypropionic acid derivative and DRF2725

the effect of stereochemistry on the potency of 120572-methoxy-120573-phenylpropanoic acids and found enzymatic racemizationof R enantiomer to the S enantiomer responsible for theobserved in vivo and in vitro equipotency of the two enan-tiomers [123]

Oguchi et al performed molecular design synthesisand hypoglycemic activity studies on the imidazopyridinederivatives of TZDs [124] In this study they developedmolecules by cyclizing the N-methylaminopyridine sidechain of RGZ resulting in imidazopyridine nucleus (seeFigure 14) Initial design synthesis and biological testingin this series gave compound 33 This compound showedpotent in vivo hypoglycemic activity but with side effects ofcardiac hypertrophy Linkers larger than methylene showedlower activity Substitution at the 5th-position of the imida-zopyridine nucleus showed an increase in the activity withchloro methoxy ethoxy benzyloxy and phenylthio groupsEspecially the methoxy substituted compound (Rivoglita-zone 34) was found to bemore potent than RGZ and showedreduced side effects compared to (33) Phase 3 clinical trialson Rivoglitazone were discontinued but its applications inxerophthalmia are being considered in a Phase 2 study [21]

Yanagisawa et al on similar lines developed oximecontaining TZD analogues (Figure 14) [125] The biphenylderivative (35) was more potent than RGZ both in vitroand in vivo assays The authors highlighted that introductionof aromatic groups methyl group on the oxime nitrogenand ethylene linker are key components leading to increasedactivity in this series of compounds

Novel pyrimidinone containing TZD derivatives werereported by Madhavan et al [126] These were derivedfrom the modification of DRF2189 (36) side chain whichhad emerged in an earlier study by the modification ofRGZ side chain [127] PMT13 (38) derived from this studyhas shown potent antihyperglycemic activity devoid of anyadverse effects in a 28-day in vivo study on Wistar rats (seeFigure 15) The 24-dimethyl substituted derivative showedlower potency than PMT13 Benzyl substitution in place ofthe ethyl group also reduced the antihyperglycemic activity

Analogues with 124-oxadiazolidine-35-dione framework inplace of TZD ring were found to be less effective in producingantihyperglycemic activity

Compound (37) with (2-furyl)-5-methyl substitution and24-oxazolidinedione head group showed better antidiabeticeffects in genetically obese and diabetic animal models(KKAy mice and Wistar fatty rats) [128] Compounds with3-arylpropyl and ethoxy spacer with para substitution werefound to be more potent than PGZ From this study therequirement of the spatial configuration of the three rings(oxazole central benzene and oxazolidinedione rings) con-nected with two alkyl spacers emerged (see Figure 15) OnlyR enantiomer of the oxazolidinedione derivatives was foundto be potent activator of PPAR120574 No racemization wasobserved under in vivo conditions in contrast to the TZDclass of compounds this is attributed to the oxygen atomin place of sulfur at the chiral center resulting in less stablecorresponding carbanion Asymmetric O-acetylation of thecorresponding 120572-hydroxyvalerate with immobilized lipasewas an important step in the synthesis of these compounds

Novel 5-aryl TZD dual PPAR120572120574 agonists were discov-ered byDesai et al in 2003 [129]They identified that a changein the position of the substitution at the central phenyl ringconverts a PPAR120574 selective agonist (39) into a dual PPAR120572120574agonist (40)

An ethylene linker along with the para substitution wasfound to be necessary for potent PPAR120574 activity Substitutionof lipophilic groups on the terminal phenyl group reduced theactivity while chloro and fluoro substituents gavemoderatelypotent dual agonists The dual agonist shown in Figure 16also showed better pharmacokinetic (PK) parameters Kimand Lee et al reported novel pyridine and purine containingTZDs for their hypoglycemic and hypolipidemic activity inKKAy mice in vivo [130 131] Substitution at the 5th positionof the pyridine ring resulted in compounds more potent thanRGZ Purine substituted analogues were found to be lesspotent than RGZ (see Figure 17)

Due to the proposed benefits mentioned previouslywith dual agonists many groups are actively developing


S

HN O

OO

N N

NR

Imidazopyridine deriatives

S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON

Oxime derivative (35)

R = H (33)R = OMe (Rivoglitazone 34)

Figure 14 Cyclization of RGZ side chain leads to the design of imidazopyridine derivatives with hypoglycemic activity and oxime derivatives

S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO

Furyl-substituted oxazolidinedione derivative (37)

Figure 15 Design of pyrimidinone derivatives from RGZ and oxazolidinedione derivatives

SAR studies for the design of dual agonists Liu et alcombined the isobutyric acid head group of fenofibric acid(46) a PPAR120572 agonist with the lipophilic aryloxy moiety of47 (see Figure 18) [132] This dual ligand (48) was found tobe more selective for PPAR120572 and inactive at other nuclearreceptors In vivo the dual agonist showed significant lower-ing of glucose levels and had dose-dependent hypolipidemiceffect Analogues with different substitution pattern at the120572 position were thus prepared Transactivation and bindingstudies revealed that bis-substitution at the aromatic ring wasessential for dual activation Extending the linker between thecarboxylic acid and the phenyl ring reduced the activity dras-tically Methoxy analogue and replacement of the isoxazolering did not significantly affect the dual activation profile

Knowledge of the clofibric acid aryloxyacetic acid andnaphthalene containing TZDs activities leads to the designof two series of 120572-aryloxypropanoic acid derivatives and an120573-aryl-120572-oxysubstituted propanoic acid [133] Both R and Senantiomers of the compounds were studied by transactiva-tion assay and only S-isomers were found to be effective inactivation both PPAR120572 and PPAR120574 Substitution of the p-chloro substituent with more lipophilic aromatic moiety (51)

improved both potency and efficacy leading to compoundswith full agonistic character towards PPAR120572 and considerableactivity against the PPAR120574 (see Figure 19) This compoundwas found be less effective in inducing adipocyte differenti-ation in vitro assays Aliphatic groups lead to an increase inactivity while introduction of polar groups on the aliphaticchain reduced the activity considerably Molecular dock-ing analysis on the previously mentioned two compoundsshowed that they bind in mostly U-shaped conformationand form hydrogen bonds with key amino acids in the AF-2 function

SAR studies on the indoleacetic acid derivatives leadto the design of dual agonists with reversed substitutionpattern (see Figure 20) [41] Initially a PAN agonist (52) wasconverted into a PPAR120572 selective agonist (53) by invertingthe substitution pattern on the indoleacetic acid derivativeAdding dimethyl substitution and moving the acidic headgroup to the 4th or 5th position on the indole ring resultedin a PPAR120572120574 dual agonists (54 and 55) The dimethylsubstitution was found to be important for PPAR120574 activationas it brought the acidic head group closer to the H-12helix leading to the formation of strong hydrogen-bonding


SNH

O

OOO

O

S

NHO

O

OO

O

PPAR120574 selective (39)

PPAR120572120574 dual (40)

Figure 16 Converting a PPAR120574 selective ligand to PPAR120574120572 dual agonist

S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R

5-Furanylpyridine TZD derivative (41)

5-Phenylpyridine TZD derivative (42)

4-Phenoxypyridine TZD derivative (43)

9-Substituted-9H-purine TZD derivatives (45)

SNH

O

O

ONN

N N

RO


Figure 17 Pyridine and purine TZD derivatives derived from RGZ

interactions with SER289 HIS323 HIS449 and TYR473 asconfirmed by crystal structure analysis

Kim et al reported SAR studies on novel benzyl thio-carbamates as dual PPAR120572120574 agonists [134] An initial studyconfirmed that thiocarbamates (56) are more potent thancarbamates (57) (Figure 21) Aromatic terminal rings likebenzyl gave potent compounds Any increase or decrease inthe chain length of this linker leads to decrease in activity Butbulkier substituents lead to an increase in PPAR120574 agonisticactivity S-isomer was found to be more active than the R-isomer towards PPAR120572 while both were found equally activeat PPAR120574 This is due to slightly larger active site volume inPPAR120574 in comparison to PPAR120572 thus both R- and S-isomers

find space inside the active site of PPAR120574 But in the caseof PPAR120572 the lipophilic region in the molecule is forced toenter in hydrophilic cavity giving a lower score as confirmedby docking analysis The presence of thiocarbamate moietywas found to be essential for dual activity as confirmed bythe PPAR120574 selectivity of the corresponding alcohol (58)

Casimiro-Garcia et al reported the effect of substitutionat the 120572-position of phenylpropanoic acids on the dualPPAR120572120574 activation (see Figure 22) [51] Replacement ofether moiety with acetylene ethylene propyl or heteroatom-based linker lead to significant changes in the affinity andtransactivation profiles In the series withmethyl group in theoxazole ring and pyrrole ring as the 120572-substituent acetylene


O

OH OH

OH

OO

Cl

OOO

N

O

OON

A potent dual agonist

F3C

F3C

2-Aryloxypropanoic acid derivativePPAR120574 selective (47)

Fenofibric acidPPAR120572 selective (46)

(48)

2-(57-dipropyl-3-(trifluoromethyl) benzo[d] isoxazol-6-yloxy)-2-methylpropanoic acid

Figure 18 Design of a dual PPAR120572120574 agonist from fenofibric acid and 2-aryloxypropanoic acid derivative

O COOH

Naphthyl derivative of clofibric acid (49)

O COOH

Cl

COOH

Cl

Biphenyl derivative (50)

O

P-chlorophenoxy derivative (51)

Figure 19 Dual PPAR120572120574 fibric acid derivatives

linker gave nonselective ligand while substitution with ethy-lene and propyl groups gave PPAR120574 selective compoundsThese compounds showed less activation of PPAR120574 as com-pared to the pyrrole-containing compound reported earlierby GlaxoSmithKline [135] S-isomers were foundmore activethan the R-isomers as reported earlier for other tyrosinebased compounds (59 and 60) [135 136] Substituents like3-pyridinyl 4-biphenyl 3-biphenyl or phenyl in place ofpyrrole drastically reduced the activity at both receptorsMolecule (61) showed lower PPAR120572 activation and wasspecifically selective for PPAR120574 This was understood to arisedue to steric interaction with TYR314 in the PPAR120572 activesite Replacement of the ether oxygen by a nitrogen reducedPPAR120574 activation

Takamura et al have performed synthesis and biologicaltesting on 120572-substituted 120573-phenylpropionic acid derivativeswith pridin-2-ylphenyl moiety for PPAR activation and anti-hyperglycemic activity [137] Oxime or amide linkers werekept in the molecules based on their earlier reported com-pound (37) [125] Propyl group at 120572 position showed potentglucose lowering activity compared to other groups like iso-propyl butyl and phenylisopropyl (62 and 63 in Figure 23)Methylthio substitution at 120572 position showed good dualagonistic activity PPAR120574 agonistic activity could not becorrelated in every molecule to its glucose lowering activityAs reported by many groups earlier S-isomer was foundto be more active in all compounds studied The authorspointed out the fact that these compounds may be selective


N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)

PPAR120572 agonist (53)

PPAR120572120574 dual agonist

4-Substituted (54)5-Substituted (55)

Figure 20 Reversal of substitution pattern in indoleacetic acid gives PPAR120572120574 dual agonist

NH

O X

COOH

OEtCOOH

OEt

OH

Alcohol derivative (58)X = S thiocarbamate (56)X = O carbamate (57)

Figure 21 Novel benzyl thiocarbamates based Dual PPAR120572120574 agonists

HO

HO

HO

ON

O

Pyrrole-based propanoic acid derivative (59)

ON

O

ON

HN

O

Propylene linker derivative (60)

Ethylamine linker derivative (61)

Figure 22 Pyrrole-based L-tyrosine derivatives with different linkers


N

NO O

COOH

O

N

O

O

COOH

O

HN

120572-phenoxy oxime derivative (62) 120572-119905Bu-phenoxy oxime derivative (63)

Figure 23 120572-substituted 120573-phenylpropionic acid derivatives with dual agonistic profiles

PPAR120574 modulators or might activate fatty acid receptors onthe pancreatic cells (GPR40FFAR) [138] Recently due to thefailure of PPAR agonists to reach market the pharmaceuticalindustry and academicians started looking at other targetsGPR40 a GPCR found on islet 120573 cell membranes is one suchtarget known to mediate the insulin secretary effect of fattyacids [139ndash142]

Chromane 2-carboxylic acid derivatives were developedbyKoyama et al for discovery of novel dual PPAR120572120574 agonists[143] Cyclization of fibrates was envisioned as the syntheticroute leading to the compoundswith chromane nucleus Sub-stitution at the 6th position of the chromane ring resulted ininactive compounds while the compounds with substitutionat the 7th position were found to be active dual agonistsCompounds with propyl liker were found more potent thanwith ethyl andmethyl linkers Propyl hydrogen and halogensubstituents resulted in potent PPAR120574 activators with mod-erate PPAR120572 activation In vitro binding and transactivationfor affinity in vivo dbdb mouse studies for antihyperglyce-mic Hamster and Dog models for pharmacokinetic studieswere utilized to select compound (64) for further studies (seeFigure 24)

Parmenon et al reported synthesis and biological evalu-ation of tetrahydroxyquinone derivatives for dual PPAR120572120574agonistic activity [144 145] Di-ester- and ether-ester-basedtetrahydroquinone derivatives were identified from thesestudies No direct correlation between the EC

50(from trans-

activation assays) and IC50

values from receptor-bindingstudies was observed This could be due to different bindingsite or interactions for the compounds under considerationand the standard (RGZ) The observed in vitro activityunfortunately did not translate into in vivo activity for thisclass of compounds

Ohashi et al have recently analyzed the effect of stere-ochemistry at the 120572 position of the phenylpropanoic acidderivatives [146] A reversal of enantiomeric activity wasobserved when a branched carbon atom is present at the 120573position with respect to the carbonyl group R enantiomerwas found to bemore active in both phenethyl and cyclohexylsubstituents while S enantiomer was more active in the ethylsubstituted compound (Figure 25) Thus authors concludedthat branched or unbranched nature of the substituentsdetermine the enantiomer selectivity Glide docking studieswere performed to support the conclusions But furthercrystallographic andmolecularmodeling studies are requiredto validate these findings

In an effort to identify CNS penetrating PPAR120574 ago-nists Virley et al at GlaxoSmithKline have discovered

O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH

Chromane nucleusFibratesPPAR120572 pharmacophore

2-Ethylchromane-2-carboxylic acid derivative (64)

Figure 24 Chromane carboxylic acid derivatives developed forPPAR120572120574 dual activation

GSK19971328B a novel partial agonist In the crystal structurebenzylamide group in this molecule was found to bind in AF-2 region where TZD ring of RGZ is known to have stabilizinginteractions A series of SAR studies were performed tounderstand the importance of substituents on each fragmentin the molecule Thus ethyl substituent on the benzylamidegroup presence of unsubstituted C2 position in benzimida-zole central ring andfluoro substitution gave compoundwithmost desirable pharmacological and pharmacokinetic profile

Majority of the SAR studies discussed previously havefocused on one scaffold or another while attempting toincrease the potency and efficacy towards the desired receptorsubtype The activity profiles observed in the SAR studiesbased on in vitro binding studies are not always reflect-ed as similar profiles in the in vivo studies due to theinvolvement of many factors during the absorption distri-bution and metabolism (ADME) that is the pharmacoki-neticspharmacodynamics (PKPD) of the drug candidatesThese PKPD factors and the corresponding tissue specific(muscle and adipose) responses lead to large variability in thepatientrsquos response to the drugThe in vitro and in vivo studiesprovide vital information about the overall profile of the drugcandidates but they cannot provide atomic and molecularlevel understanding of the interactions between the drug andthe macromolecular protein targets which are at the heartof the final biologically observed response Such electronicatomic and molecular level information on the interactionbetween the drug candidate and the target macromoleculecan be obtained from structure-based and computer-aideddrug discovery methodologies A review of these efforts for


COOHCOOH

O

NH

O

120572-ethyl substituted phenylpropanoic acid

O

NH

O

120572- phenethyl substituted phenylpropanoic acidderivative (S) enantiomer more active derivative (R) enantiomer more active

(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF

GSK1997132B120572-cyclohexyl substituted phenylpropanoic acidderivative (R) enantiomer more active

(R)

(b)

Figure 25 (a) Stereochemistry-activity relationship in a series of substituted phenylpropanoic acid derivatives (b) A CNS penetratingbenzimidazole derivative

the discovery of PPAR120574 ligands is presented in the nextsection

5 Computational Approaches forthe Discovery of PPAR120574 Ligands

Drug discovery and development is a very time and resourcedemanding process in which a continuous exchange of infor-mation and knowledge takes place at the design and develop-mental stagesThis generally involves a period of 10 to 15 yearsand 10 to 15 $billion (these figures tend to vary dependingon the therapeutic area but a general increase is seen withtime) Thus computational predictive tools available in thephysical chemical and biological scientific community areextensively utilized for making quick as well as well-thoughtstrategic decisions In the late phases of drug discovery forexample clinical trials statistical tools aremore often utilizedto understand the hidden trends in the data On the otherend of the spectrum where target identification validationmolecular design and interactions of drug candidates withtargets are to be understood computer-aided drug design(CADD) approaches are often employed [147]

CADD methods generally employ a combination of thefollowing methodologies (1) two-dimensional quantitativestructure activity relationship (2DQSAR) (2) 3D and higher-dimensional QSAR methods (3) pharmacophore mappingand virtual screening (4) molecular docking in proteincrystal structures (or homology models) (5) receptor-basedQSARmethods (6) receptor-based pharmacophoremappingand virtual screening (7) de novo drug design (8) moleculardynamics simulations and (9) quantum chemical methods

Reports making used of one or more such methodologies aredescribed in the following

QSAR methods based on 2D information are employedwhen the data set contains large variation in the chemicalstructures of the ligands under consideration as in the case forPPAR120574 [148ndash150] Rucker et al reported a 2D QSAR analysisof PPAR120574 ligands employing a set of molecular descrip-tors supplied in the program MOE The descriptors likeatom and bond counts connectivity indices partial chargedescriptors pharmacophoric feature descriptors calculatedphysical property descriptors and MACCS keys were usedin the analysis Data selection was based on the type ofassay to derive meaningful correlation models The receptorbinding studies (p119870

119894) from the scintillation proximity assay

and transactivation data from transient cotransfection assaywere employed in the generation of models Compoundswere randomly partitioned into a training set (90) andtest set (10) Four 2D QSAR equations were generated andthoroughly validated (i) multiple linear regression (MLR)(ii) genetic algorithm variable selection module of MOE forreceptor binding (iii)MLR equation for gene transactivationand (iv) activity-activity (receptor binding versus transactiva-tion data) relationship The authors concluded that variationin the central part of the ligand seemed to have minorimportance in comparison to the other pharmacophoricfeatures (acidic head group and hydrophobic tail) Utilizingonly 2D structural features of the ligands although can allowmolecules of diverse nature to be included in the analysisit potentially leads to oversimplifications about the structureactivity relationships Thus more robust 3D structural infor-mation about molecules can be considered while developing


structure activity relationships Efforts in this direction arepresented in the following paragraphs

QSAR methods like comparative molecular momentanalysis (CoMMA) [151] comparative molecular field anal-ysis (CoMFA) [152] molecular similarity indices in a com-parative analysis (CoMSIA) [153] and adaptation of fields formolecular comparison (AFMoC) [154] make use of the 3Dstructural information of ligands to build correlations withbiological activity Khanna et al have utilized a novel conceptof additivity of molecular fields using the CoMFA approachto develop dualmodels for PPAR120572 andPPAR120574 dual activation[100] In this study the authors reported individualmodels forPPAR120572 and PPAR120574 activities and a dual model by summingthe in vitro activity data thus generating the dual modelThisdual model was shown to be superior to individual PPAR120572and PPAR120574models in predicting the dual activation Generalstructure for the data set is shown in Figure 26 Individualmodels retained their ability to make reasonable individualactivity predictions These models were able to predict dualand selective activation for both receptors Utility of thesemodels in the drug design was shown by confirming thepredictions of the model using molecular docking analysisand analyzing importantH-bonding interactions in the activesite The authors highlighted the importance of using dualmodel in combination with the individual models to avoidmisleading conclusions This is because the sum of activitiesfor two molecules can be identical in spite of having verydifferent individual activities

A modified receptor-based QSAR study on the same setof molecules was reported by Lather et al later [155] Volumein the active site occupied by the ligands (119881site) was shown asan important parameter in developing the QSAR equationsUtilizing the same dataset as used by Khanna et al [100]they developed selective and dual models with the additionof 119881site Molecular descriptors like constitutional topological(Zagreb and Balaban-type index) geometrical electrostaticand quantum chemical (CODESSA) were employed in thisstudy Balaban-type index performed better in comparisonto the Zagreb index The three models pointed out thedifferences in structural characteristics of PPAR120572 and PPAR120574ligands For PPAR120572 activity size and hydrophobicity of theligands play a major role while electrostatic and H-bondinginteractions were found to contribute more to the PPAR120574activation The authors claimed that limitations arising fromthe CoMFA requirements namely prior alignment of 3Dstructures could be avoided by using their method of QSARThe PPAR120574 model of Lather et al showed that with anincrease in the number of double bonds there is a decreasein the activity This corroborates with lower activity ofthe endogenous PPAR120574 ligands which have polyunsaturatedframework (Figure 26)

In the quest to find novel insulin sensitizing moleculesthat can avoid toxicities associated with TZD class of drugsmany research groups have looked towards other chemicalclass with similar pharmacophoric features A few 3D QSARstudies have been reported on such compounds Rathi et alhave employed Apex-3D software to determine primary andsecondary binding characteristics in L-tyrosine analoguesnecessary for PPAR120574 activation (Figure 26) [156]

Brown et al have used the concept of biased chemicallibraries for screening of compounds for PPAR activation[157] A library of 480 compounds was made using a combi-nation of three phenoxyisobutyric acid derivatives along withdifferent amines and isocyanate derivatives to generate ureaanaloguesThe library was screened using cell-based reportergene assay for PPAR-GAL4 chimeric receptors A PPAR120575specific compound (GW2433 Figure 26) was identified dur-ing the screening PPAR120572 showed most promiscuous natureamong the three receptors by binding to more than 50 ofthe compounds screened while PPAR120574 and PPAR120575 showedlarger selectivity profiles The authors interpreted this resultas PPAR120572 having a special physiological role in maintaininglipid metabolism due to its presence in the liver

A structure-based drug design strategy was employedby Kuhn et al to identify dual PPAR120572120574 activators [39]The indole-based scaffold (Figure 26) was selected fromthe in-house database with the hydrophobic central proteinenvironment as a constraint while maintaining syntheticaccessibility and drug-like properties In the SAR study effectof various structural features like position of the propionicacid chain attached to the indole scaffold length of the linkerbetween the indole and the oxazole ring influence of varioussubstituents on the activity were investigated An increasein the size of the terminal substituents leads to an increasein the PPAR120572 affinity while it decreased the PPAR120574 affinityThese findings can be used to fine-tune the selectivity of PPARligands

Scarsi et al performed in vitro binding and transac-tivation studies on sulfonylurea class of drug moleculesfor potential PPAR120574 activation [158] Gliquidone Glipizideand Nateglinide activated PPAR120574 at physiologically relevantconcentrations Common pharmacophoric features based onp119870119886values were suggested as the basis for PPAR120574 activation

(see Figure 27) Based on these findings and molecular dock-ing studies the authors suggested novelmolecules (eg 70) byremoving noninteracting nitrogen atom of the sulfonylureagroup for further investigations

Markt et al performed pharmacophore mapping and vir-tual screening study on PPAR ligands [159] Structure-basedpharmacophore models (based on the active site differences)were reported for PPAR120572 and PPAR120575 while a ligand-basedpharmacophore model was reported for PPAR120574 Structure-based model was found less effective for PPAR120574 due to thesmall number of receptor complexes in comparison to thenumber of known ligands for this receptor subtype at thattime With larger number of crystal structures availablenow a better receptor based pharmacophore model canbe developed Models specific for PPAR120572 agonists PPAR120574agonists PPAR120574 partial agonists and PPAR120575 agonists weredeveloped using 18 21 5 and 7 compounds respectivelyThese models were validated using a set of 357 structurallydiverse sets of PPAR ligands divided into 321 actives and 36inactives For the PPAR120572 and PPAR120575 the structure-basedmodels were refined using the ligand-based pharmacophoremodels This was done by the removal of extra hydrophobicfeature form the structure based models In the next stepthe authors used an in-house pharmacophore databaseldquoInteLigand databaserdquo consisting of 1537 structure-based


NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O

Indole propionic acids derivative

R1

X = S5-aryl thiazolidinedione (65)X = Ooxazolidinedione (66)

N-(2-benzoylphenyl)-L-tyrosine derivatives

Figure 26 Molecules used to develop 3D CoMFA models of PPAR activity and novel PPAR120574 agonists discovered using QSAR and virtualscreening approaches

SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)

X = NH (glimepiride 69)X = C (C-glimepiride 70)

(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)

Figure 27 (a) Sulfonylureas glinides and N-sulfonyl carboxamides as potential PPAR120574 activators (b) Pharmacophoric features common incarboxylic acids TZDs and sulfonamides

models for 181 pharmacological targets for parallel screeningstudy Using a perl script and the target score numbers oftargets hit by the same set of ligands were identified Forone-third of the PPAR ligands PPARs were identified as thefirst target while for 26 of the ligands P450 2C9was the firsttarget Other protein targets identifiedwereHRV coat protein

and only RXR120573 from the rest of the nuclear receptor familyThus this study has proven the utility of parallel screeningfor determining the correct target for a set of compounds

Giaginis et al have analyzed correlations between lipo-philic properties and the activities of PPAR120574 ligands [160]A potential PPAR120574 ligand targeted for therapy should have


in addition to the pharmacophoric features a right balancebetween lipophilic and hydrophilic group dispositions in themolecule TZD and L-tyrosine class of compounds had anoptimum logP and logD values in the range 0ndash2 They high-lighted the fact that although natural ligands of PPAR120574 arelipophilic long-chain carboxylic acids there is no statisticalcorrelation between pEC

50pIC50and logPlogD values

Structure-based de novo design approach was employedby Dong et al to identify PPAR120574 ligands Ragaglitazarcrystal structure was used to build the receptor-based modelMultiple copy simultaneous search (MCSS) and LeapFrog denovo design programs were employed to find the favorableorientation of indole-based derivatives in the active site Twoout of ten molecules thus identified compound (71) showedreceptor-binding affinities similar to RGZ (see Figure 28)

Structure-based virtual screening approach wasemployed by Salam et al for identifying PPAR120574 agonistsInduced fit docking protocol was utilized for this purposeThis lead to the discovery of 120595-baptigenin (72) (Figure 28)and other flavonoids as potent PPAR120574 agonists [161]Similarly pharmacophore-based virtual screeningmethodology was employed for the identification ofnatural-product-derived PPAR120574 ligands by Tanrikulu etal [162] Crystal structures for RGZ Ragaglitazar andTesaglitazar were used in the study to develop receptor-basedmodel using software LIQUID [163] In vitro binding assaysconfirmed the validity of such screening approach where 73(Figure 28) was identified as potent PPAR120574 activator

A combination of pharmacophore mapping and QSARmodel development was utilized by Al-Najjar et al forthe discovery of a new nanomolar PPAR120574 activator [164]Ligand-based methods using CATALYST-HYPOGEN [165]were employed for generating pharmacophoric maps Thepharmacophoric space was explored by applying structuralboundaries Final analysis gave 104 models which weresubsequently used in QSAR modeling The QSAR equa-tion consisted of 4 pharmacophore hypotheses molecularfractional polar surface area (FPSA) number of rotatablebonds and hydrogen bond donor (HBD) Comparison withcrystallographic complexes (2Q59 2G0G and 2P4Y) wasperformed to validate themodels NCI database was screenedusing CATALYST Lipniskirsquos rule of five and Verberrsquos rulewere applied to filter the resulting hits In vitro transactivationassay confirmed 3 molecules to be potent PPAR120574 activatorsFigure 28 shows one of them (74)

Sundriyal et al have performed virtual screening usingCATALYST program for the identification of novel PPAR120574ligands [166] Crystal structure (2PRG) with RGZ cocom-plexed with PPAR120574 ligand-binding domain was employedto generate query structure Three pharmacophoric featurescharacteristic of PPAR120574 ligands (i) two hydrogen bondacceptor (ii) hydrophobic aromatic feature assigned to thecentral ring and (iii) hydrophobic aromatic feature assignedto the side chain were employed along with the querystructure to screen the NCI and Maybridge databases Outof the 46 and 13 hits obtained from the NCI and Maybridgedatabases barbituric acid derivatives (11 see Figure 29) per-fectly mapped on the query and pharmacophoric features

These results were further validated using FlexX molecu-lar docking study In vitro and in vivo studies [167] haveconfirmed the PPAR120574 binding and antidiabeticantiobesityeffects of this class of compounds Using a closely relatedreplacement of acidic head group of Farglitazar Sundriyalet al identified novel PPAR120574 activators Molecular dock-ing using FlexX and receptor-binding affinity studies wereemployed to confirm the PPAR120574 binding 2-Hydroxy-14-naphthoquinone derivatives (Figure 29) were identified aspotent PPAR120574 activators from this study Phenyl nitrileand fluoro substituted derivatives showed significant bindingaffinity compared to PGZ [168]

Important pharmacophoric features for pan agonistswere analyzed by Sundriyal and Bharatam using HipHopprogram [169] Seven pharmacophoric features were used togenerate a hypothesis ldquohypo-1rdquoThis hypothesis predicted panagonistic character with 913 success rate for highly activecompounds The success rates for corresponding active andmoderately active compounds were lower Hydrogen bondacceptor feature (HBA) was found to be most critical for thediscrimination of actives from inactives Virtual screeningwith hypo-1 gave hits with large molecular weight Thus theauthors modified this hypothesis by deleting less importantfeatures one at a time leading to hits with more drug-likeproperties Molecular docking was employed to understandthe interaction profiles for these hits

The ldquosumof activitiesrdquo concept was extended by Sundriyaland Bharatam to pan PPAR agonists [170] In this study theauthors developed CoMFA based 120572 120574 and 120575 and summodelsusing a data set of 39 compounds divided into training setof 28 and test set of 11 compounds The sum model hadmolecular fields similar to 120572 and 120574 models The sum modelwas used to design novel molecules with better predictedldquooverall activityrdquo and docking scores

Ligand and receptor centric 3D shape methods of vir-tual screening were combined by Choi et al to identify13-diphenyl-1H-pyrazole and (120573-carboxyethyl)-rhodaninederivatives as novel PPAR120574 agonists [171] Four partial ago-nists and three full agonists were used to build the ligandsbased 3D queries which were used to screen a library of1000 compounds Receiver-operating characteristic (ROCS)combo score was employed for the screening In the receptorcentric method shape-based distributed docking in the cog-nate PPAR120574 crystal structure of the class representing ligandwas performed Fluorescent protein (FP) transactivationassay and receptor-binding studies were performed on 50virtually selected compounds SP3300 (75) and SP1818 (76)were identified as a novel partial and full agonists from thesestudies (Figure 28) A CoMFA study based on the dockingpose of the most potent compound was performed to under-stand QSAR in this series and to design new compounds

A de novorational approach was utilized in the identifi-cation of isoxazolyl-serine-based PPAR agonists [172] Usingthe already existing SAR for PPAR ligands these agonistswere developed Some of the weak agonists of PPAR120574 wereobserved to stimulate cardiomyocyte differentiation frommurine ES cells PPAR120572 agonists fenofibrate Wy-14643and PPAR120574 as well as PPAR120575 agonists RGZ GW1929 andGW501516 were found inactive in this assayThus the authors


O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)

Indole-based PPAR120574 agonist (71) 120595-baptigenin (72)

NO2

Figure 28 Indole-based (de novo design) pyrazole-based rhodanine derivatives and natural-product-derived PPAR120574 agonists

Barbituric acid derivatives

NH

OHN

O

OO

2-hydroxy-14-naphthoquinone derivatives

O

OHO

R

R

Figure 29 Barbituric acid and 2-hydroxy-14-naphthoquinone derivatives discovered as PPAR120574 agonists using a combination CADDapproaches

concluded that PPAR activation is not the primary targetfor the ligand-induced cardiomyocyte differentiation Thispoints to the fact that ligands with PPAR activation butlacking cardiotoxic profiles could be developed

Molecular docking studies using GOLD software wereperformed by Kaya et al to develop a screening approachfor the identification of phthalate monoester-based PPAR120574activators [173] Initial docking experiments confirmed thatnear native conformations were predicted for PPAR120574 ligandswith 6ndash8 rotatable bonds (RGZ Ragaglitazar TesaglitazarFarglitazar and GW409544) but for ligands with largernumber of rotatable bonds (partial agonist GW0072) manyconformational clusters were generated by the docking pro-gram Strong correlation (1198772 062 and 082) between EC

50

and the docking scorerescored CHARMMACE energieswas obtained But the authors emphasized the fact that this isdue to restricting to a small dataset and highlighted the factthat correlations between binding affinity transactivationalactivity and binding score are not seen in larger and diversedatasets For example GW0072 has larger activity than RGZbut based on more decisive transactivational data and invivo the former is partial agonist and the later a full agonistThese anomalies and lacunae in the understanding of PPARactivation result from the neglect of dynamic state of thereceptor-ligand interactions associated energetics and therole of H-12 helix dynamics in the function of PPARs

Considering the fact that most of the natural ligandsof PPARs are fatty acids Maltarollo and Honorio havecalculated molecular properties of different fatty acids andmade an attempt to correlate them with PPAR activity [174]Optimum ranges for molecular properties like molecularweight (250ndash310) molecular volume (950ndash1200 A3) logP(50ndash65) number of carbon atoms (16ndash20) and hydrationenergies (lt minus10 kcalmol) were found for PPAR activationUnsaturation increased activity in molecules with similarnumber of carbon atoms Authors suggested the use of theseparameters while considering novel ligand development

Recently a combination of core hopping approachmolec-ular docking and molecular dynamics has been utilized byMa et al for the design novel dual agonists [175] Structureof GW409544 was divided into three core substructures Fivedifferent fragments for each corewere selected from theZINCdatabase by utilizing the ldquoprotocore preparationrdquo module inSchrodinger 2009Then a core hopping approachwas utilizedto generate 1 times 5 times 5 = 25 different compounds Crystalstructures of PPAR120572 (1K7L) and PPAR120574 (1 K74) were utilizedfor performing glide docking of these novel compoundsBased on the docking score comp 1 and comp8 (Figure 30)were selected for molecular dynamics studies Complex ofPPAR120572 and PPAR120574 with comp 1 showed significant stabi-lization of the backbone RMSD and AF-2 function whilecomplex of comp8 showed significant RMSD fluctuations in


O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

Figure 30 Dual agonist comp 1 identified from GW409544 using core hopping docking and MD approach

both regions These results agreed with the relative bindingaffinity predicted by docking

To summarize in the past decade a large number ofstructural scaffolds have been identified to show selectiveactivation of the PPAR class of receptors Many of the leadsthus recognized have shown promising pharmacologicalprofiles But long-term safety and in vivo efficacy haveremained the major challenging aspects in the developmentof novel molecules for the treatment of diabetes Thus inaddition to having a deeper understanding of SAR andQSAR of novel class of molecules focus must be equallyplaced on optimizing drug-like properties pharmacody-namicpharmacokinetic parameters of drug candidates andclinical end points in the diabetic patients

6 Dynamics of PPAR120574 and Its Relation toActivation and Antidiabetic Effects

The ligand-binding domain (LBD) of PPAR120574 consists of 270amino acids and as discussed in Section 32 and shown inTable 2Figure 5 PPAR120574 has a large Y-shaped active siteExcept the region around the AF-2 (H-12 helix) most ofthe interactions within the active site are hydrophobic innature [16] This causes the receptor to be very dynamic andlarge variations in the active site volume can be seen in thecrystal structures published (Tables 2 and 3) A comparisonof the apo and ligand (RGZ) bound PPAR120574 crystal structuresreveals the fact that the H-12 helix in the activation function(AF-2) can take two conformations ldquoopenrdquo and ldquoclosedrdquo [16]Backbone RMS value of 145 A was found between the twostructures Small RMS values for the backbone alignmentsuggest that the overall structural fold is maintained inthe bound and unbound structures While the RMS valuefor backbone atoms of the H-12 helix (residues 466ndash476)between the two structures was found to be 477 A Thussignificant differences are seen in the disposition of the H-12helix in the various states accessible to the receptor In the apostate theH-12 helix can take twopositions ldquoopenrdquo and ldquoclosedrdquowhile in the presence of agonist the closed conformationof the H-12 helix is stabilized significantly (Figure 31) Thischaracteristic is a common feature of most of the nuclearreceptors [49] In the closed state the significant interactionsof H-12 helix with the H-3 and H-10 helices are observed giv-ing additional stability to the conformation [16 19] Presenceof charge clamp interactions between residues in the H-12(GLU471) and H3 (LYS301) helices with residues in the coac-tivators gives further stabilization in the closed conformation

H-12 helix closedconformation (2PRG)

H-12 helix openconformation (1PRG)

Figure 31 Apo (1PRG) and RGZ (2PRG) bound crystal structuresof PPAR120574 overlaid (RMS backbone atoms = 145 A) H-12 helix in theapo structure takes the open conformation while in the RGZ boundstructure (2PRG) theH-12 helix is in closed state RMS forH-12 helixbackbone atoms is 477 A

Due to these characteristic interactions full or partialagonistic behavior of various ligands was explained earlierbased on H-12 helix dynamics and led to the design andsynthesis of large number of structural scaffolds (Section 5)[21 25 42 49 176] Ligands interacting with the H-12helix and polar amino acids in the AF-2 region showedfull agonistic character while ligands with weaker or nointeractions with the H-12 helix showed moderate to partialagonistic behavior Earlier Willson et al have correlatedthe binding affinity of ligands with the antihyperglycemicactivity [115] But this agonistic nature of the ligands do notalways correlated with antidiabetic activity quantitatively[177 178] Thus the exact mechanism of activation of PPAR120574and its relation to antidiabetic effects remains to be unclear

Failure of the dual SPPARMs and other molecules toreach the market calls for a fresh look at the molecular mech-anism by which different endogenoussynthetic ligands andcorepressorscoactivators of different PPAR receptors func-tion to give a myriad of responses under different physio-logical conditions It has been postulated that differentligands interact with the PPAR receptors resulting in ligandspecific conformational changes These differences translate


into selective recruitment of cofactors (corepressors andcoactivators) giving ligand specific gene expression patternsMolecular dynamics (MD) simulations which are used to fol-low the properties of a system as a function of time coupledwith rigid and flexible dockingmethods can really bridge thisgap between the structurally diverse set of known ligands anda broad range of in vitro and in vivo activity profiles

Considering the dynamic behavior of PPAR120574 and flexi-bility in its natural ligands it becomes important to find theconformational space and freedom that the natural ligandshave in the active site of PPAR120574 Thus it can be suggestedthat any ligand which is expected to have similar effectsshould have the conformational landscape similar to thesenatural ligands for optimal activity In the family of nuclearreceptors role of the H-12 helix in the activation of thereceptor is generally recognized Full agonists are known tobind with the H-12 helix leading to the complete activationof the receptor Partial agonists on the other hand areproposed to activate the receptor partially by binding inother end of the active site and have minimal interactionwith the H-12 helix Similar hypotheses have been made inthe literature regarding the activation of PPAR120574 by full andpartial agonists But the crystal structure data (see Table 3)available for PPAR120574 suggests that the distinction is not sosimple asmany partial agonists bind to or near theH-12 helixand have important hydrogen-bonding interactions with theamino acids innear H-12 helix Hence a clear understandingof the agonistic character of ligands based on the interactionswithin the active site is missing or obscure in the literature

MD simulations were performed by Jyrkkarinne et alrecently to understand the agonistic and inverse agonisticbehavior of constitutive androstane receptor (CAR) ligands[179] Genest et al have performed MD simulations on per-oxisome proliferator-activated receptor 120574 (PPAR120574) a nuclearreceptor in order to elucidate the ligand escape trajectoriesfrom the bound state [180]They also showed that the ligandslike GW0072 make use of the intrinsic flexibility in theprotein structure to maneuver in the active site Anotherreport on ligand specificity molecular switch and interac-tions with regulators has tried to reassess the importanceof various interactions of ligands (using MD studies) withPPAR and reiterated the fact that the interactions of acidicgroups although are important for efficient activity are notthe sole factor in determining the partial or full agonisticnature of the ligands [181] Other important interactionsin the Y-shaped cavity of PPAR120574 are hydrophobic and 120587-stacking interactions Similarly MD simulation studies byMichalik et al have reanalyzed the role of the AF-2 regionand other amino acids in the active site of PPAR120572 [176] Inanother study MD simulations were performed with twoureidofibrate-like enantiomers and confirmed stabilizationof the H-12 helix by the more active S-isomer [182] Ji andZhang highlighted the importance of protein polarizationand electrostatic interactions in the AF-2 functional domain[97] All these reports have substantiated the fact that fullpotential of the interactions in the active site have not beenexplored for this very important antidiabetic target and MDsimulations can give useful insights into the receptor-ligandinteractions and agonistic character of a ligand

Choi et al have alternatively suggested that the inhibitionof phosphorylation of PPAR120574 at SER273 by cyclin-dependentkinase (Cdk5) could be mediating the beneficial antidiabeticeffects of PPAR120574 agonists like RGZ andMRL24 [177] SER273(SER274 in 2PRG structure) is located in a loop between thehelices H3 and H4 and occupies the surface opposite to theAF-2 region in the PPAR120574 active site [16 19]MRL24 a partialagonist reduced the dynamic nature of the H3 helix (AAs309ndash315) 120573-sheet region (369ndash379) and SER273 RGZ wasfound to have less effect on the dynamics of these regions butreduced the dynamics of H-12 H-11 helix and AF-2 regionsignificantly

Based on these results Choi et al have suggested thedevelopment of novel ligand with three important charac-teristics namely (1) high affinity for PPAR120574 (2) blockingof Cdk5-mediated PPAR120574 phosphorylation and (3) lack ofclassical agonism [178] A novel indole-containing benzoicacid derivative (SR1664) was developed which stabilized theH-3 and 120573-sheet regions of the receptor while increasing thedynamical nature of the H-11 helix This ligand shows mini-mal effect on the dynamics of H-12 helix As expected fromthe dynamical nature of the H-12 helix SR1664 did not showany classical agonistic character Gene expression patterns ofSR1664 overlapped only partially with that of RGZ directingtowards beneficial and harmful genes expression patternsGenes like aP2 Adipsin Cd24a and so forth were expressedat higher level with SR1664 than with RGZ while genes likePdk4 Hsdl2 and so forth showed opposite expression levelsOn the other handRGZ and SR1664 showed similar effects onthe expression of genes like Adiponectin Nr1d2 Ddx17 andso forth Further studies are thus required to fully understandthe implications of these results for understanding PPARbiology and to drug discovery efforts

Recently Amato et al have reported 5-(5-bromo-2-methoxy-benzylidene)-3-(4-methyl-benzyl)-thiazolidine-24-dione (GQ-16) as a novel partial agonist promotinginsulin sensitization without the side effects of weight gain[88] Crystallographic studies showed that this compoundbinds near the 120573-sheet region like MRL24 and BVT13Inhibition of Cdk5-mediated phosphorylation of SER273was observed and proposed as a possible explanation for itspartial PPAR120574 activation and antidiabetic activity

7 Conclusions and Future Directions onDeveloping Novel Ligands

More than a decade has passed since the introduction of TZDclass of drugs in the market but still a guided developmentof a novel drug with ideal balance of controlling glucoselevels and simultaneously avoiding the side effects relatedto cardiovascular system and toxicity remains a challengingtaskThis is a combined effect of incomplete understanding ofbiology of the PPAR120574 its in vitro and in vivo interactions withpotential drug candidates and correlation of these factorswith clinically beneficial effects

Nevertheless both SAR and CADD approaches haveplayed a vital role in the identification of novel scaffoldswith improved PPAR activation profiles Glitazars new TZD


derivatives L-tyrosine-based analogues sulfonamide deriva-tives sulfonylureas barbituric acid derivatives 2-hydroxyn-aphthoquinones indoleacetic acid derivatives propionic acidderivatives oxazolidindiones and 120572-substituted propanoicacid derivatives represent the remarkable success achieved sofar in this area Both ligand and receptor-basedmethods havecontributed to this success

Novel virtual screening techniques pharmacophoremodels coupled with recent QSAR approaches better meth-ods of estimating binding affinities and advances in under-standing the dynamics of PPAR120574-ligand interaction by em-ploying molecular dynamics simulations have raised newhopes towards finding ligands with better pharmacologicalprofiles

Recently discovered alternate mechanisms of antidia-betic actions of PPAR120574 ligands via inhibition of Cdk5-mediated phosphorylation have given new impetus to effortsfor the discovery of novel PPAR120574 ligands as antidiabeticagents Overlap in the gene expression patterns (Section 4)of classical agonists (RGZ) and ligands (SR1664) inhibitingphosphorylation (but lacking classical agonism) suggests thatpartial agonists with inhibitory effects on phosphorylationcould prove more effective Thus retaining partial agonisticcharacter with specific gene expression patterns could provebeneficial These beneficial genes could be clustered fromexpression patterns of the already known ligands A numberof recent studies have begun to identify and cluster suchgene sets [177 178 183 184] This suggests that ligandswith following characteristic should be developed (1) partialagonist of PPAR120574 (2) potent inhibitor of Cdk-5-mediatedphosphorylation at SER273 of PPAR120574 and (3) high-bindingaffinity for PPAR120574

Abbreviations

(PPAR120574) Peroxisome proliferator-activated receptor120574



(TZD) Thiazolidinedione(RGZ) Rosiglitazone(PGZ) Pioglitazone(TGZ) Troglitazone(SPPARM) Selective PPAR modulators(SAR) Structure activity relationship(QSAR) Quantitative structure activity relationship(CADD) Computer-aided drug discoveryGOLD (Genetic algorithm optimized ligand

docking)(ROCS) Receiver-operating characteristic(GLP-1) Glucagon like peptide-1(MCP-1) Monocyte chemoattractant protein-1

Conflict of Interests

Authors declare that they have no conflict of interests

Acknowledgments

Authors are thankful to the Council of Scientific and Indus-trial Research (CSIR) New Delhi India for financial sup-port

References

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[2] B Pourcet J C Fruchart B Staels and C Glineur ldquoSelectivePPAR modulators dual and pan PPAR agonists multimodaldrugs for the treatment of type 2 diabetes and atherosclerosisrdquoExpert Opinion on Emerging Drugs vol 11 no 3 pp 379ndash4012006

[3] R H van Huijsduijnen W H B Sauer A Bombrun and DSwinnen ldquoProspects for inhibitors of protein tyrosine phospha-tase 1B as antidiabetic drugsrdquo Journal of Medicinal Chemistryvol 47 no 17 pp 4142ndash4146 2004

[4] D E Moller ldquoNew drug targets for type 2 diabetes and themetabolic syndromerdquo Nature vol 414 no 6865 pp 821ndash8272001

[5] C DeSouza and V Fonseca ldquoTherapeutic targets to reducecardiovascular disease in type 2 diabetesrdquo Nature Reviews DrugDiscovery vol 8 pp 361ndash367 2009

[6] N Cho and Y Momose ldquoPeroxisome proliferator-activatedreceptor 120574 agonists as insulin sensitizers from the discovery torecent progressrdquo Current Topics in Medicinal Chemistry vol 8pp 1483ndash1507 2008

[7] B Panunti A A Jawa and V A Fonseca ldquoMechanisms andtherapeutic targets in type 2 diabetes mellitusrdquo Drug DiscoveryToday Disease Mechanisms vol 1 no 2 pp 151ndash157 2004

[8] D K Arulmozhi and B Portha ldquoGLP-1 based therapy for type 2diabetesrdquo European Journal of Pharmaceutical Sciences vol 28no 1-2 pp 96ndash108 2006

[9] JM Lehmann L BMoore T A Smith-OliverWOWilkisonT M Willson and S A Kliewer ldquoAn antidiabetic thiazolidine-dione is a high affinity ligand for peroxisome proliferator-activated receptor 120574 (PPAR120574)rdquo Journal of Biological Chemistryvol 270 no 22 pp 12953ndash12956 1995

[10] C J Rosen ldquoThe rosiglitazone storymdashlessons from an FDAadvisory committee meetingrdquo The New England Journal ofMedicine vol 357 pp 844ndash846 2007

[11] M T Smith ldquoMechanisms of troglitazone hepatotoxicityrdquoChemical Research in Toxicology vol 16 no 6 pp 679ndash6872003

[12] M Chandran S A Phillips T Ciaraldi and R R Henry ldquoAdi-ponectin more than just another fat cell hormonerdquo DiabetesCare vol 26 no 8 pp 2442ndash2450 2003

[13] A H Knoll ldquoThe early evolution of eukaryotes a geologicalperspectiverdquo Science vol 256 no 5057 pp 622ndash627 1992

[14] M E Greene B Blumberg O W McBride et al ldquoisolation ofthe human peroxisome proliferator activated receptor gammacDNA expression in hematopoietic cells and chromosomalmappingrdquo Gene Expression vol 4 no 4-5 pp 281ndash299 1995

[15] B Desvergne andW Wahli ldquoPeroxisome proliferator-activatedreceptors nuclear control of metabolismrdquo Endocrine Reviewsvol 20 no 5 pp 649ndash688 1999

[16] R T Nolte G B Wisely S Westin et al ldquoLigand binding andco-activator assembly of the peroxisome proliferator-activatedreceptor-120574rdquo Nature vol 395 no 6698 pp 137ndash143 1998


[17] M Hendlich F Rippmann and G Barnickel ldquoLIGSITE auto-matic and efficient detection of potential small molecule-bind-ing sites in proteinsrdquo Journal of Molecular Graphics and Model-ling vol 15 no 6 pp 359ndash363 1997

[18] ldquoThe PyMOL Molecular Graphics System Version 1501rdquoSchrodinger LLC

[19] V Chandra P Huang Y Hamuro et al ldquoStructure of the intactPPAR-120574-RXR-120572 nuclear receptor complex on DNArdquo Naturevol 456 no 7220 pp 350ndash356 2008

[20] T Sohda K Mizuno E Imamiya H Tawada K Meguro andY Kawamatsu Yamamoto ldquoStudies on antidiabetic agents III5-arylthiazolidine-2 4-diones as potent aldose reductase inhib-itorsrdquo Chemical and Pharmaceutical Bulletin vol 30 pp 3601ndash3616 1982

[21] C Pirat A Farce N Lebegue et al ldquoTargeting peroxisomeproliferator-activated receptors (PPARs) development of mod-ulatorsrdquoMedicinal Chemistry vol 55 no 9 pp 4027ndash4061 2012

[22] R T Gampe Jr V GMontana M H Lambert et al ldquoAsymme-try in the PPAR120574RXR120572 crystal structure reveals the molecularbasis of heterodimerization among nuclear receptorsrdquoMolecu-lar Cell vol 5 no 3 pp 545ndash555 2000

[23] H E XuMH Lambert VGMontana et al ldquoMolecular recog-nition of fatty acids by peroxisome proliferator-activated recep-torsrdquoMolecular Cell vol 3 no 3 pp 397ndash403 1999

[24] P Cronet J F W Petersen R Folmer et al ldquoStructure of thePPAR120572 and -120574 ligand binding domain in complex with AZ 242ligand selectivity and agonist activation in the PPAR familyrdquoStructure vol 9 no 8 pp 699ndash706 2001

[25] H E XuMH Lambert V GMontana et al ldquoStructural deter-minants of ligand binding selectivity between the peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 98 no24 pp 13919ndash13924 2001

[26] H E Xu T B Stanley V G Montana et al ldquoStructural basisfor antagonist-mediated recruitment of nuclear co-repressorsby PPAR120572rdquo Nature vol 415 no 6873 pp 813ndash817 2002

[27] P Sauerberg I Pettersson L Jeppesen et al ldquoNovel tricyclic-120572-alkyloxyphenylpropionic acids dual PPAR120572120574 agonists withhypolipidemic and antidiabetic activityrdquo Journal of MedicinalChemistry vol 45 no 4 pp 789ndash804 2002

[28] S Ebdrup I Pettersson H B Rasmussen et al ldquoSynthesisand biological and structural characterization of the dual-actingperoxisome proliferator-activated receptor 120572120574 agonist ragagli-tazarrdquo Journal of Medicinal Chemistry vol 46 no 8 pp 1306ndash1317 2003

[29] T Ostberg S Svensson G Selen et al ldquoA new class of peroxi-some proliferator-activated receptor agonists with a novel bind-ing epitope shows antidiabetic effectsrdquo Journal of BiologicalChemistry vol 279 no 39 pp 41124ndash41130 2004

[30] I Takada R T Yu H E Xu et al ldquoAlteration of a single aminoacid in peroxisome proliferator-activated receptor-120572 (PPAR120572)generates a PPAR120575 phenotyperdquo Molecular Endocrinology vol14 no 5 pp 733ndash740 2000

[31] G Q Shi J F Dropinski B M McKeever et al ldquoDesign andsynthesis of 120572-aryloxyphenylacetic acid derivatives a novelclass of PPAR120572120574 dual agonists with potent antihyperglycemicand lipid modulating activityrdquo Journal of Medicinal Chemistryvol 48 no 13 pp 4457ndash4468 2005

[32] Y Li M Choi K Suino et al ldquoStructural and biochemicalbasis for selective repression of the orphannuclear receptor liverreceptor homolog 1 by small heterodimer partnerrdquo Proceedings

of the National Academy of Sciences of the United States ofAmerica vol 102 no 27 pp 9505ndash9510 2005

[33] N Mahindroo C F Huang Y H Peng et al ldquoNovelindole-based peroxisome proliferator-activated receptor ago-nists design SAR structural biology and biological activitiesrdquoJournal of Medicinal Chemistry vol 48 no 26 pp 8194ndash82082005

[34] S A Fyffe M S Alphey L Buetow et al ldquoRecombinant humanPPAR-120573120575 ligand-binding domain is locked in an activatedconformation by endogenous fatty acidsrdquo Journal of MolecularBiology vol 356 no 4 pp 1005ndash1013 2006

[35] S A Fyffe M S Alphey L Buetow et al ldquoReevaluation of thePPAR-120573120575 ligand binding domain model reveals why it exhibitsthe activated formrdquoMolecular Cell vol 21 no 1 pp 1ndash2 2006

[36] N Mahindroo C C Wang C C Liao et al ldquoIndol-1-yl aceticacids as peroxisome proliferator-activated receptor agonistsdesign synthesis structural biology and molecular dockingstudiesrdquo Journal of Medicinal Chemistry vol 49 no 3 pp 1212ndash1216 2006

[37] E Burgermeister A Schnoebelen A Flament et al ldquoA novelpartial agonist of peroxisome proliferator-activated receptor-120574(PPAR120574) recruits PPAR120574-coactivator-1120572 prevents triglycerideaccumulation and potentiates insulin signaling in vitrordquoMolec-ular Endocrinology vol 20 no 4 pp 809ndash830 2006

[38] I L Lu C F Huang Y H Peng et al ldquoStructure-based drugdesign of a novel family of PPAR120574 partial agonists virtualscreening X-ray crystallography and in vitroin vivo biologicalactivitiesrdquo Journal of Medicinal Chemistry vol 49 no 9 pp2703ndash2712 2006

[39] B Kuhn H Hilpert J Benz et al ldquoStructure-based design ofindole propionic acids as novel PPAR120572120574 co-agonistsrdquo Bioor-ganic amp Medicinal Chemistry Letters vol 16 no 15 pp 4016ndash4020 2006

[40] C R Hopkins S V OrsquoNeil M C Laufersweiler et al ldquoDesignand synthesis of novel N-sulfonyl-2-indole carboxamides aspotent PPAR-120574 binding agents with potential application to thetreatment of osteoporosisrdquo Bioorganic amp Medicinal ChemistryLetters vol 16 no 21 pp 5659ndash5663 2006

[41] N Mahindroo Y H Peng C H Lin et al ldquoStructural basis forthe structure-activity relationships of peroxisome proliferator-activated receptor agonistsrdquo Journal ofMedicinal Chemistry vol49 no 21 pp 6421ndash6424 2006

[42] G Pochetti C Godio N Mitro et al ldquoInsights into the mech-anism of partial agonism crystal structures of the peroxisomeproliferator-activated receptor 120574 ligand-binding domain in thecomplex with two enantiomeric ligandsrdquo Journal of BiologicalChemistry vol 282 no 23 pp 17314ndash17324 2007

[43] R Epple M Azimioara R Russo et al ldquo345-trisubstitutedisoxazoles as novel PPAR120575 agonists Part 2rdquoBioorganicampMedic-inal Chemistry Letters vol 16 no 21 pp 5488ndash5492 2006

[44] H Oon Han S H Kim K H Kim et al ldquoDesign and synthesisof oxime ethers of 120572-acyl-120573-phenylpropanoic acids as PPARdual agonistsrdquo Bioorganic amp Medicinal Chemistry Letters vol17 pp 937ndash941 2007

[45] A L B Ambrosio S M G Dias I Polikarpov R B Zurier SH Burstein and R C Garratt ldquoAjulemic acid a synthetic non-psychoactive cannabinoid acid bound to the ligand bindingdomain of the human peroxisome proliferator-activated recep-tor 120574rdquo Journal of Biological Chemistry vol 282 no 25 pp 18625ndash18633 2007

[46] M Einstein T E Akiyama G A Castriota et al ldquoThe differen-tial interactions of peroxisome proliferator-activated receptor 120574


ligandswithTyr473 is a physical basis for their unique biologicalactivitiesrdquo Molecular Pharmacology vol 73 no 1 pp 62ndash742008

[47] M L Sierra V Beneton A B Boullay et al ldquoSubstituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPAR120572 ago-nists 1 Discovery of a novel series of potent HDLc raisingagentsrdquo Journal of Medicinal Chemistry vol 50 no 4 pp 685ndash695 2007

[48] R P Trump J E Cobb B G Shearer et al ldquoCo-crystal structureguided array synthesis of PPAR120574 inverse agonistsrdquo Bioorganic ampMedicinal Chemistry Letters vol 17 no 14 pp 3916ndash3920 2007

[49] J B Bruning M J Chalmers S Prasad et al ldquoPartial agonistsactivate PPAR120574 using a helix 12 independent mechanismrdquoStructure vol 15 no 10 pp 1258ndash1271 2007

[50] I Pettersson S Ebdrup M Havranek et al ldquoDesign of a partialPPAR120575 agonistrdquo Bioorganic amp Medicinal Chemistry Letters vol17 no 16 pp 4625ndash4629 2007

[51] A Casimiro-Garcia C F Bigge J A Davis et al ldquoEffects ofmodifications of the linker in a series of phenylpropanoic acidderivatives synthesis evaluation as PPAR120572120574 dual agonistsand X-ray crystallographic studiesrdquo Bioorganic and MedicinalChemistry vol 16 no 9 pp 4883ndash4907 2008

[52] T Itoh L Fairall K Amin et al ldquoStructural basis for the acti-vation of PPAR120574 by oxidized fatty acidsrdquo Nature Structural ampMolecular Biology vol 15 no 9 pp 924ndash931 2008

[53] S Keil H Matter K Schonafinger et al ldquoSulfonylthiadiazoleswith an unusual binding mode as partial dual peroxisome pro-liferator-activated receptor (PPAR) 120574120575 agonists with highpotency and in vivo efficacyrdquo ChemMedChem vol 6 pp 633ndash653 2011

[54] C Weidner J C de Groot A Prasad et al ldquoAmorfrutins arepotent antidiabetic dietary natural productsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 109 pp 7257ndash7262 2012

[55] T Waku T Shiraki T Oyama et al ldquoStructural insight intoPPAR120574 activation through covalent modification with endoge-nous fatty acidsrdquo Journal ofMolecular Biology vol 385 no 1 pp188ndash199 2009

[56] TWaku T Shiraki T Oyama KMaebara R Nakamori andKMorikawa ldquoThe nuclear receptor PPAR120574 individually respondsto serotonin- and fatty acid-metabolitesrdquo The EMBO Journalvol 29 pp 3395ndash3407 2010

[57] T Oyama K Toyota TWaku et al ldquoAdaptability and selectivityof human peroxisome proliferator-activated receptor (PPAR)pan agonists revealed from crystal structuresrdquo Acta Crystallo-graphica Section D vol 65 no 8 pp 786ndash795 2009

[58] T Waku T Shiraki T Oyama and K Morikawa ldquoAtomicstructure of mutant PPAR120574 LBD complexed with 15d-PGJ2novel modulation mechanism of PPAR120574RXR120572 function bycovalently bound ligandsrdquo FEBS Letters vol 583 no 2 pp 320ndash324 2009

[59] M Ohashi T Oyama I Nakagome et al ldquoDesign synthesisand structural analysis of phenylpropanoic acid-type PPAR120574-selective agonists discovery of reversed stereochemistry-activ-ity relationshiprdquo Journal of Medicinal Chemistry vol 54 no 1pp 331ndash341 2011

[60] KWakabayashi SHayashi YMatsui et al ldquoPharmacology andin vitro profiling of a novel peroxisome proliferator-activatedreceptor 120574 ligand cerco-Ardquo Biological amp Pharmaceutical Bul-letin vol 34 no 7 pp 1094ndash1104 2011

[61] R Montanari F Saccoccia E Scotti et al ldquoCrystal structureof the peroxisome proliferator-activated receptor 120574 (PPAR120574)ligand binding domain complexed with a novel partial agonista new region of the hydrophobic pocket could be exploited fordrug designrdquo Journal of Medicinal Chemistry vol 51 no 24 pp7768ndash7776 2008

[62] H Zhang D E Ryono P Devasthale et al ldquoDesign synthesisand structure-activity relationships of azole acids as novelpotent dual PPAR 120572120574 agonistsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 19 pp 1451ndash1456 2009

[63] Y Li A Kovach K Suino-Powell D Martynowski and H EXu ldquoStructural and biochemical basis for the binding selectivityof peroxisome proliferator-activated receptor 120574 to PGC-1120572rdquoJournal of Biological Chemistry vol 283 no 27 pp 19132ndash191392008

[64] Y Li J Zhang F J Schopfer et al ldquoMolecular recognition ofnitrated fatty acids by PPAR120574rdquo Nature Structural amp MolecularBiology vol 15 no 8 pp 865ndash867 2008

[65] B G Shearer H S Patel A N Billin et al ldquoDiscovery of a novelclass of PPAR120575 partial agonistsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 18 no 18 pp 5018ndash5022 2008

[66] D R Artis J J Lin C Zhang et al ldquoScaffold-based discoveryof indeglitazar a PPAR pan-active anti-diabetic agentrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 1 pp 262ndash267 2009

[67] U Grether A Benardeau J Benz et al ldquoDesign and bio-logical evaluation of novel balanced dual PPAR120572120574 agonistsrdquoChemMedChem vol 4 no 6 pp 951ndash956 2009

[68] A Motani Z Wang J Weiszmann et al ldquoINT131 a selectivemodulator of PPAR120574rdquo Journal ofMolecular Biology vol 386 no5 pp 1301ndash1311 2009

[69] A Benardeau J Benz A Binggeli et al ldquoAleglitazar a newpotent and balanced dual PPAR120572120574 agonist for the treatmentof type II diabetesrdquo Bioorganic amp Medicinal Chemistry Lettersvol 19 no 9 pp 2468ndash2473 2009

[70] C H Lin Y H Peng M S Coumar et al ldquoDesign and struc-tural analysis of novel pharmacophores for potent and selectiveperoxisome proliferator-activated receptor 120574 agonistsrdquo Journalof Medicinal Chemistry vol 52 no 8 pp 2618ndash2622 2009

[71] R V Connors Z Wang M Harrison et al ldquoIdentification of aPPAR120575 agonist with partial agonistic activity on PPAR120574rdquo Bioor-gan-ic amp Medicinal Chemistry Letters vol 19 no 13 pp 3550ndash3554 2009

[72] G Fracchiolla A Laghezza L Piemontese et al ldquoNew 2-aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors 120572120574 dual agonists with improved potencyand reduced adverse effects on skeletal muscle functionrdquoJournal of Medicinal Chemistry vol 52 no 20 pp 6382ndash63932009

[73] A Casimiro-Garcia C F Bigge J A Davis et al ldquoSynthesis andevaluation of novel 120572-heteroaryl-phenylpropanoic acid deriv-atives as PPAR120572120574 dual agonistsrdquo Bioorganic and MedicinalChemistry vol 17 no 20 pp 7113ndash7125 2009

[74] Y Li Z Wang N Furukawa et al ldquoT2384 a novel antidiabeticagent with unique peroxisome proliferator-activated receptor 120574binding propertiesrdquo Journal of Biological Chemistry vol 283 no14 pp 9168ndash9176 2008

[75] J Li L J Kennedy Y Shi et al ldquoDiscovery of an oxyben-zylglycine based peroxisome proliferator activated receptor120572 selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxa-zol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid


(BMS-687453)rdquo Journal of Medicinal Chemistry vol 53 no 7pp 2854ndash2864 2010

[76] A Furukawa T Arita S Satoh et al ldquoDiscovery of a novel selec-tive PPAR120574 modulator from (-)-cercosporamide derivativesrdquoBioorganic amp Medicinal Chemistry Letters vol 20 pp 2095ndash2098 2010

[77] A RiuMGrimaldi A leMaire et al ldquoPeroxisome proliferator-activated receptor 120574 is a target for halogenated analogs of bis-phenol Ardquo Environmental Health Perspectives vol 119 no 9 pp1227ndash1232 2011

[78] C A Luckhurst L A Stein M Furber et al ldquoDiscovery ofisoindoline and tetrahydroisoquinoline derivatives as potentselective PPAR120575 agonistsrdquo Bioorganic amp Medicinal ChemistryLetters vol 21 no 1 pp 492ndash496 2011

[79] A Riu A leMaireM Grimaldi et al ldquoCharacterization of nov-el ligands of ER120572 Er120573 and PPAR120574 the case of halogenatedbisphenol A and their conjugated metabolitesrdquo ToxicologicalSciences vol 122 pp 372ndash382 2011

[80] K A Evans B G Shearer D DWisnoski et al ldquoPhenoxyaceticacids as PPAR120575 partial agonists synthesis optimization and invivo efficacyrdquo Bioorganic ampMedicinal Chemistry Letters vol 21pp 2345ndash2350 2011

[81] J Uppenberg C Svensson M Jaki G Bertilsson L Jendebergand A Berkenstam ldquoCrystal structure of the ligand bindingdomain of the human nuclear receptor PPAR120574rdquo Journal ofBiological Chemistry vol 273 no 47 pp 31108ndash31112 1998

[82] H Zhang X Xu L Chen et al ldquoMolecular determinants ofmagnolol targeting both RXR120572 and PPAR120574rdquo PloS ONE vol 6Article ID e28253 2011

[83] A Casimiro-Garcia G F Filzen D Flynn et al ldquoDiscovery ofa series of imidazo[45-b]pyridines with dual activity at angiot-ensin II type 1 receptor and peroxisome proliferator-activatedreceptor-120574rdquo Journal of Medicinal Chemistry vol 54 no 12 pp4219ndash4233 2011

[84] L Porcelli F Gilardi A Laghezza et al ldquoSynthesis characteri-zation and biological evaluation of ureidofibrate-like derivativesendowedwith peroxisome proliferator-activated receptor activ-ityrdquo Journal of Medicinal Chemistry vol 55 pp 37ndash54 2012

[85] M Sime A C Allan P Chapman et al ldquoDiscovery ofGSK1997132B anovel centrally penetrant benzimidazole PPAR120574partial agonistrdquo Bioorganic amp Medicinal Chemistry Letters vol21 pp 5568ndash5572 2011

[86] A C Puhl A Bernardes R L Silveira et al ldquoMode of perox-isome proliferator-activated receptor 120574 activation by luteolinrdquoMolecular Pharmacology vol 81 no 6 pp 788ndash799 2012

[87] W Liu F Lau K Liu et al ldquoBenzimidazolones a new class ofselective peroxisome proliferator-activated receptor 120574 (PPAR120574)modulatorsrdquo Journal of Medicinal Chemistry vol 54 pp 8541ndash8554 2011

[88] A A Amato S Rajagopalan J Z Lin et al ldquoGQ-16 a novelperoxisome proliferator-activated receptor 120574 (PPAR120574) ligandpromotes insulin sensitizationwithout weight gainrdquoThe Journalof Biological Chemistry vol 287 pp 28169ndash28179 2012

[89] R R Malapaka S Khoo J Zhang et al ldquoIdentification andmechanism of 10-carbon fatty acid as modulating ligand ofperoxisome proliferator-activated receptorsrdquo The Journal ofBiological Chemistry vol 287 pp 183ndash195 2012

[90] A Furukawa T Arita T Fukuzaki et al ldquoSubstituents at thenaphthalene C3 position of (-)-cercosporamide derivatives sig-nificantly affect themaximal efficacy as PPAR120574 partial agonistsrdquo

BioorganicampMedicinal Chemistry Letters vol 22 pp 1348ndash13512012

[91] N Kuwabara T Oyama D Tomioka et al ldquoPeroxisome pro-liferator-activated receptors (PPARS) have multiple bindingpoints that accommodate ligands in various conformationsphenylpropanoic acid-type PPAR ligands bind to PPAR indifferent conformations depending on the subtyperdquo Journal ofMedicinal Chemistry vol 55 pp 893ndash902 2012

[92] Y Amano T Yamaguchi K Ohno et al ldquoStructural basisfor telmisartan-mediated partial activation of PPAR gammardquoHypertension Research vol 35 pp 715ndash719 2012

[93] J L Oberfield J L Collins C P Holmes et al ldquoA peroxisomeproliferator-activated receptor 120574 ligand inhibits adipocyte dif-ferentiationrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 96 no 11 pp 6102ndash6106 1999

[94] T S Hughes M J Chalmers S Novick et al ldquoLigand andreceptor dynamics contribute to the mechanism of gradedPPAR120574 agonismrdquo Structure vol 20 pp 139ndash150 2012

[95] R S Chana A J Lewington and N J Brunskill ldquoDifferentialeffects of peroxisome proliferator activated receptor-120574 (PPAR120574)ligands in proximal tubular cells thiazolidinediones are partialPPAR120574 agonistsrdquo Kidney International vol 65 no 6 pp 2081ndash2090 2004

[96] K Yamagishi K Yamamoto Y Mochizuki T Nakano S Yama-da and H Tokiwa ldquoFlexible ligand recognition of peroxi-some proliferator-activated receptor-120574 (PPAR120574)rdquo Bioorganic ampMedicinal Chemistry Letters vol 20 no 11 pp 3344ndash3347 2010

[97] C G Ji and J Z H Zhang ldquoProtein polarization is criticalto stabilizing AF-2 and helix-21015840 domains in ligand binding toPPAR-120574rdquo Journal of the American Chemical Society vol 130 no50 pp 17129ndash17133 2008

[98] K Henriksen I Byrjalsen P Qvist et al ldquoEfficacy and safetyof the PPAR120574 partial agonist balaglitazone compared with pio-glitazone and placebo a phase III randomized parallel-groupstudy in patients with type 2 diabetes on stable insulin therapyrdquoDiabetesMetabolism Research and Reviews vol 27 no 4 pp392ndash401 2011

[99] PMisra R Chakrabarti R K Vikramadithyan et al ldquoPAT5A apartial agonist of peroxisome proliferator-activated receptor 120574 isa potent antidiabetic thiazolidinedione yet weakly adipogenicrdquoJournal of Pharmacology and Experimental Therapeutics vol306 no 2 pp 763ndash771 2003

[100] S Khanna M E Sobhia and P V Bharatam ldquoAdditivity ofmolecular fields CoMFA study ondual activators of PPAR120572 andPPAR120574rdquo Journal ofMedicinal Chemistry vol 48 no 8 pp 3015ndash3025 2005

[101] C Fievet J-C Fruchart and B Staels ldquoPPAR120572 and PPAR120574 dualagonists for the treatment of type 2 diabetes and the metabolicsyndromerdquo Current Opinion in Pharmacology vol 6 pp 606ndash614 2006

[102] I Ahmed K Furlong J Flood V P Treat and B J GoldsteinldquoDual PPAR 120572120574 agonists promises and pitfalls in type 2 diabe-tesrdquo American Journal of Therapeutics vol 14 no 1 pp 49ndash622007

[103] Y Xu C J Rito G J Etgen et al ldquoDesign and synthesis of120572-aryloxy-120572-methylhydrocinnamic acids a novel class of dualperoxisome proliferator-activated receptor 120572120574 agonistsrdquo Jour-nal of Medicinal Chemistry vol 47 no 10 pp 2422ndash2425 2004


[104] B CHansen X T TignoA BenardeauMMeyer E Sebokovaand J Mizrahi ldquoEffects of aleglitazar a balanced dual perox-isome proliferator-activated receptor 120572120574 agonist on glycemicand lipid parameters in a primate model of the metabolicsyndromerdquo Cardiovascular Diabetology vol 10 p 7 2011

[105] S L Cox ldquoTesaglitazar a promising approach in type 2 diabe-tesrdquo Drugs of Today vol 42 no 3 pp 139ndash146 2006

[106] D Conlon ldquoGoodbye glitazarsrdquo British Journal of Diabetes ampVascular Disease vol 6 no 3 pp 135ndash137 2006

[107] L S Higgins and A M DePaoli ldquoSelective peroxisome prolif-erator-activated receptor 120574 (PPAR120574) modulation as a strategyfor safer therapeutic PPAR120574 activationrdquo The American Journalof Clinical Nutrition vol 91 pp 267Sndash272S 2009

[108] S Rocchi F Picard J Vamecq et al ldquoA unique PPAR120574 ligandwith potent insulin-sensitizing yet weak adipogenic activityrdquoMolecular Cell vol 8 no 4 pp 737ndash747 2001

[109] T Allen F Zhang S A Moodie et al ldquoHalofenate is a selectiveperoxisome proliferator-activated receptorgamma modulatorwith antidiabetic activityrdquoDiabetes vol 55 no 9 pp 2523ndash25332006

[110] T Fujimura C Kimura T Oe et al ldquoA selective peroxisomeproliferator-activated receptor 120574modulator with distinct fat cellregulation propertiesrdquo Journal of Pharmacology and Experimen-tal Therapeutics vol 318 no 2 pp 863ndash871 2006

[111] T Tagami H Yamamoto KMoriyama et al ldquoA selective perox-isome proliferator-activated receptor-120574modulator telmisartanbinds to the receptor in a different fashion from thiazolidine-dionesrdquo Endocrinology vol 150 no 2 pp 862ndash870 2009

[112] H A Pershadsingh and TW Kurtz ldquoInsulin-sensitizing effectsof telmisartan implications for treating insulin-resistant hyper-tension and cardiovascular diseaserdquo Diabetes Care vol 27 no4 p 1015 2004

[113] J Rieusset F Touri L Michalik et al ldquoA new selective peroxi-some proliferator-activated receptor 120574 antagonist with antiobe-sity and antidiabetic activityrdquoMolecular Endocrinology vol 16no 11 pp 2628ndash2644 2002

[114] H MWright C B Clish T Mikami et al ldquoA synthetic antago-nist for the peroxisomeproliferator-activated receptor 120574 inhibitsadipocyte differentiationrdquo Journal of Biological Chemistry vol275 no 3 pp 1873ndash1877 2000

[115] T M Willson J E Cobb D J Cowan et al ldquoThe structuremdashactivity relationship between peroxisome proliferator-activatedreceptor 120574 agonism and the antihyperglycemic activity of thia-zolidinedionesrdquo Journal of Medicinal Chemistry vol 39 no 3pp 665ndash668 1996

[116] K A Reddy B B Lohray V Bhushan et al ldquoNovel antidiabeticand hypolipidemic agents 5 Hydroxyl versus benzyloxy con-taining chroman derivativesrdquo Journal of Medicinal Chemistryvol 42 no 17 pp 3265ndash3278 1999

[117] K Matsumoto S Miyake M Yano Y Ueki and Y TominagaldquoIncrease of lipoprotein (a) with troglitazonerdquo The Lancet vol350 no 9093 pp 1748ndash1749 1997

[118] K Kawai Y Kawasaki-Tokui T Odaka et al ldquoDisposition andmetabolism of the new oral antidiabetic drug troglitazone inrats mice and dogsrdquo Arzneimittel-Forschung vol 47 no 4 pp356ndash368 1997

[119] B B Lohray V B Lohray A C Bajji et al ldquo(-)3-[4-[2-(phenox-azin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(-)DRF2725] a dual PPAR agonist with potent antihyperglycemic andlipid modulating activityrdquo Journal of Medicinal Chemistry vol44 no 16 pp 2675ndash2678 2001

[120] D A Brooks G J Etgen C J Rito et al ldquoDesign and syn-thesis of 2-methyl-2-4-[2-(5-methyl-2-aryloxazol-4-yl)ethox-y]phenoxypropionic acids a new class of dual PPAR120572120574 ago-nistsrdquo Journal of Medicinal Chemistry vol 44 no 13 pp 2061ndash2064 2001

[121] T Sohda KMizuno andY Kawamatsu ldquoStudies on antidiabet-ic agents VI Asymmetric transformation of (plusmn)-5-[4-(1-meth-ylcyclohexylmethoxy)benzyl]-24-thiazolidinedione (ciglita-zone) with optically active 1-phenylethylaminesrdquo Chemical andPharmaceutical Bulletin vol 32 no 11 pp 4460ndash4465 1984

[122] P V Bharatam and S Khanna ldquoRapid racemization in thia-zolidinediones a quantum chemical studyrdquo Journal of PhysicalChemistry A vol 108 no 17 pp 3784ndash3788 2004

[123] D Haigh G Allen H C Birrell et al ldquoNon-thiazolidinedioneantihyperglycaemic agents Part 3 the effects of stereochemistryon the potency of 120572-methoxy-120573-phenylpropanoic acidsrdquo Bioor-ganic and Medicinal Chemistry vol 7 no 5 pp 821ndash830 1999

[124] M Oguchi K Wada H Honma et al ldquoMolecular designsynthesis and hypoglycemic activity of a series of thiazolidine-24-dionesrdquo Journal of Medicinal Chemistry vol 43 no 16 pp3052ndash3066 2000

[125] H Yanagisawa M Takamura E Yamada et al ldquoNovel oximeshaving 5-benzyl-24-thiazolidinedione as antihyperglycemicagents synthesis and structure-activity relationshiprdquoBioorganicampMedicinal Chemistry Letters vol 10 no 4 pp 373ndash375 2000

[126] G R Madhavan R Chakrabarti R K Vikramadithyan et alldquoSynthesis and biological activity of novel pyrimidinone con-taining thiazolidinedione derivativesrdquoBioorganic andMedicinalChemistry vol 10 no 8 pp 2671ndash2680 2002

[127] B B Lohray V Bhushan B P Rao et al ldquoNovel euglycemic andhypolipidemic agentsrdquo Journal of Medicinal Chemistry vol 41no 10 pp 1619ndash1630 1998

[128] Y Momose T Maekawa T Yamano et al ldquoNovel 5-substituted24-thiazolidinedione and 24-oxazolidinedione derivatives asinsulin sensitizers with antidiabetic activitiesrdquo Journal ofMedic-inal Chemistry vol 45 no 7 pp 1518ndash1534 2002

[129] R C Desai W Han E J Metzger et al ldquo5-Aryl thiazolidine-24-diones discovery of PPAR dual 120572120574 agonists as antidiabeticagentsrdquo Bioorganic amp Medicinal Chemistry Letters vol 13 no16 pp 2795ndash2798 2003

[130] B Y Kim J B Ahn H W Lee et al ldquoSynthesis and antihy-perglycemic activity of erythrose ribose and substituted pyrrol-idine containing thiazolidinedione derivativesrdquo Chemical andPharmaceutical Bulletin vol 51 no 3 pp 276ndash285 2003

[131] H W Lee Y K Bok B A Joong et al ldquoMolecular design syn-thesis and hypoglycemic and hypolipidemic activities of novelpyrimidine derivatives having thiazolidinedionerdquo EuropeanJournal ofMedicinal Chemistry vol 40 no 9 pp 862ndash874 2005

[132] K Liu L Xu J P Berger et al ldquoDiscovery of a novel series ofperoxisome proliferator-activated receptor120572120574 dual agonists forthe treatment of type 2 diabetes and dyslipidemiardquo Journal ofMedicinal Chemistry vol 48 no 7 pp 2262ndash2265 2005

[133] A Pinelli C Godio A Laghezza et al ldquoSynthesis biologicalevaluation and molecular modeling investigation of new chiralfibrates with PPAR120572 and PPAR120574 agonist activityrdquo Journal ofMedicinal Chemistry vol 48 no 17 pp 5509ndash5519 2005

[134] N J Kim K O Lee B W Koo et al ldquoDesign synthesis andstructure-activity relationship of carbamate-tethered aryl pro-panoic acids as novel PPAR120572120574 dual agonistsrdquo Bioorganic ampMedicinal Chemistry Letters vol 17 no 13 pp 3595ndash3598 2007

[135] K G Liu M H Lambert A H Ayscue et al ldquoSynthesis andbiological activity of L-tyrosine-based PPAR120574 agonists with


reduced molecular weightrdquo Bioorganic amp Medicinal ChemistryLetters vol 11 no 24 pp 3111ndash3113 2001

[136] B R Henke S G Blanchard M F Brackeen et al ldquoN-(2-benzoylphenyl)-L-tyrosine PPAR120574 agonists 1 Discovery of anovel series of potent antihyperglycemic and antihyperlipi-demic agentsrdquo Journal of Medicinal Chemistry vol 41 no 25pp 5020ndash5036 1998

[137] M Takamura M Sakurai E Yamada et al ldquoSynthesis and bio-logical activity of novel 120572-substituted 120573-phenylpropionic acidshaving pyridin-2-ylphenylmoiety as antihyperglycemic agentsrdquoBioorganic and Medicinal Chemistry vol 12 no 9 pp 2419ndash2439 2004

[138] Y Itoh Y Kawamata M Harada et al ldquoFree fatty acids regulateinsulin secretion from pancreatic 120573 cells through GPR40rdquoNature vol 422 pp 173ndash176 2003

[139] E Christiansen CUrbanNMerten et al ldquoDiscovery of potentand selective agonists for the free fatty acid receptor 1 (FFA1GPR40) a potential target for the treatment of type II diabetesrdquoJournal of Medicinal Chemistry vol 51 pp 7061ndash7064 2008

[140] E Christiansen M E Due-Hansen and T Ulven ldquoA rapid andefficient Sonogashira protocol and improved synthesis of freefatty acid 1 (FFA1) receptor agonistsrdquo Journal of Organic Chem-istry vol 75 no 4 pp 1301ndash1304 2010

[141] S B Bharate K V Nemmani and R A VishwakarmaldquoProgress in the discovery and development of small-moleculemodulators of G-protein-coupled receptor 40 (GPR40FFA1FFAR1) an emerging target for type 2 diabetesrdquo Expert OpiniononTherapeutic Patents vol 19 pp 237ndash264 2009

[142] S Y Lu Y J Jiang J Lv T X Wu Q S Yu and W L Zhu JldquoMolecular docking andmolecular dynamics simulation studiesof GPR40 receptor-agonist interactionsrdquo Journal of MolecularGraphics and Modelling vol 28 no 8 pp 766ndash774 2010

[143] H Koyama D J Miller J K Boueres et al ldquo(2R)-2-ethylchro-mane-2-carboxylic acids discovery of novel PPAR120572120574 dual ago-nists as antihyperglycemic andhypolipidemic agentsrdquo Journal ofMedicinal Chemistry vol 47 no 12 pp 3255ndash3263 2004

[144] C Parmenon J Guillard D H Caignard et al ldquo44-dimethyl-1234-tetrahydroquinoline-based PPAR120572120574 agonists Part IIsynthesis and pharmacological evaluation of oxime and acidichead group structural variationsrdquo Bioorganic amp MedicinalChemistry Letters vol 19 no 10 pp 2683ndash2687 2009

[145] C Parmenon J Guillard D H Caignard et al ldquo44-Dimethyl-1234-tetrahydroquinoline-based PPAR120572120574 agonists PartI synthesis and pharmacological evaluationrdquo Bioorganic ampMedicinal Chemistry Letters vol 18 no 5 pp 1617ndash1622 2008

[146] M Ohashi I Nakagome J-i Kasuga et al ldquoDesign syn-thesis and in vitro evaluation of a series of 120572-substitutedphenylpropanoic acid PPAR120574 agonists to further investigate thestereochemistrymdashactivity relationshiprdquo Bioorganic ampMedicinalChemistry vol 20 no 21 pp 6375ndash6383 2012

[147] I M Kapetanovic ldquoComputer-aided drug discovery and devel-opment (CADDD) in silico-chemico-biological approachrdquoChemico-Biological Interactions vol 171 no 2 pp 165ndash1762008

[148] CHansch DHoekman A Leo DWeininger andCD Selass-ie ldquoChem-bioinformatics comparative QSAR at the interfacebetween chemistry and biologyrdquo Chemical Reviews vol 102 no3 pp 783ndash812 2002

[149] C Hansch D Hoekman and H Gao ldquoComparative QSARtoward a deeper understanding of chemicobiological interac-tionsrdquo Chemical Reviews vol 96 no 3 pp 1045ndash1075 1996

[150] S P Gupta ldquoQSAR studies on enzyme inhibitorsrdquo ChemicalReviews vol 87 no 5 pp 1183ndash1253 1987

[151] B D Silverman and D E Platt ldquoComparative molecularmoment analysis (coMMA) 3D-QSAR without molecularsuperpositionrdquo Journal of Medicinal Chemistry vol 39 no 11pp 2129ndash2140 1996

[152] R D Cramer D E Patterson and J D Bunce ldquoComparativemolecular field analysis (CoMFA) 1 Effect of shape on bindingof steroids to carrier proteinsrdquo Journal of the American ChemicalSociety vol 110 no 18 pp 5959ndash5967 1988

[153] G Klebe U Abraham and T Mietzner ldquoMolecular similarityindices in a comparative analysis (CoMSIA) of drug moleculesto correlate and predict their biological activityrdquo Journal ofMedicinal Chemistry vol 37 no 24 pp 4130ndash4146 1994

[154] H Gohlke and G Klebe ldquoDrugscoremeets CoMFA adaptationof fields for molecular comparison (AFMoC) or how to tailorknowledge-based pair-potentials to a particular proteinrdquo Jour-nal of Medicinal Chemistry vol 45 no 19 pp 4153ndash4170 2002

[155] V Lather V Kairys and M X Fernandes ldquoQuantitative struc-ture-activity relationship models with receptor-dependentdescriptors for predicting peroxisome proliferator-activatedreceptor activities of thiazolidinedione and oxazolidinedionederivativesrdquo Chemical Biology and Drug Design vol 73 no 4pp 428ndash441 2009

[156] L Rathi S K Kashaw A Dixit G Pandey and A K SaxenaldquoPharmacophore identification and 3D-QSAR studies in N-(2-benzoyl phenyl)-L-tyrosines as PPAR120574 agonistsrdquo Bioorganicand Medicinal Chemistry vol 12 no 1 pp 63ndash69 2004

[157] P J Brown T A Smith-Oliver P S Charifson et al ldquoIdentifica-tion of peroxisome proliferator-activated receptor ligands froma biased chemical libraryrdquo Chemistry and Biology vol 4 no 12pp 909ndash918 1997

[158] M ScarsiM Podvinec A Roth et al ldquoSulfonylureas and glinid-es exhibit peroxisome proliferator-activated receptor 120574 activitya combined virtual screening and biological assay approachrdquoMolecular Pharmacology vol 71 no 2 pp 398ndash406 2007

[159] P Markt D Schuster J Kirchmair C Laggner and T LangerldquoPharmacophore modeling and parallel screening for PPARligandsrdquo Journal of Computer-Aided Molecular Design vol 21no 10-11 pp 575ndash590 2007

[160] C Giaginis S Theocharis and A Tsantili-Kakoulidou ldquoA con-sideration of PPAR-120574 ligands with respect to lipophilicity cur-rent trends and perspectivesrdquo Expert Opinion on InvestigationalDrugs vol 16 no 4 pp 413ndash417 2007

[161] N K Salam T H Huang B P Kota M S Kim Y Li and D EHibbs ldquoNovel PPAR-gamma agonists identified from a naturalproduct library a virtual screening induced-fit docking andbiological assay studyrdquoChemical Biology amp Drug Design vol 71no 1 pp 57ndash70 2008

[162] Y Tanrikulu O Rau O Schwarz et al ldquoStructure-based phar-macophore screening for natural-product-derived PPAR120574 ago-nistsrdquo ChemBioChem vol 10 no 1 pp 75ndash78 2009

[163] Y Tanrikulu M Nietert U Scheffer et al ldquoScaffold hoppingby rdquofuzzyrdquo pharmacophores and its application to RNA targetsrdquoChemBioChem vol 8 no 16 pp 1932ndash1936 2007

[164] B O Al-Najjar H A Wahab T S Tengku A C Shu-ChienN A Ahmad and M O Taha ldquoDiscovery of new nanomolarperoxisome proliferator-activated receptor 120574 activators via elab-orate ligand-based modelingrdquo European Journal of MedicinalChemistry vol 46 no 6 pp 2513ndash2529 2011


[165] D Barnum J Greene A Smellie and P Sprague ldquoIdentificationof common functional configurations among moleculesrdquo Jour-nal of Chemical Information and Computer Sciences vol 36 no3 pp 563ndash571 1996

[166] S Sundriyal B Viswanad P Ramarao A K Chakrabortiand P V Bharatam ldquoNew PPAR120574 ligands based on barbituricacid virtual screening synthesis and receptor binding studiesrdquoBioorganic amp Medicinal Chemistry Letters vol 18 no 18 pp4959ndash4962 2008

[167] H Zheng S Li L Ma et al ldquoA novel agonist of PPAR-120574 basedon barbituric acid alleviates the development of non-alcoholicfatty liver disease by regulating adipocytokine expression andpreventing insulin resistancerdquo European Journal of Pharmacol-ogy vol 659 no 2-3 pp 244ndash251 2011

[168] S Sundriyal B Viswanad E Bharathy P Ramarao A K Chak-raborti and P V Bharatam ldquoNew PPAR120574 ligands based on2-hydroxy-14-naphthoquinone computer-aided design syn-thesis and receptor-binding studiesrdquo Bioorganic amp MedicinalChemistry Letters vol 18 pp 3192ndash3195 2008

[169] S Sundriyal and P V Bharatam ldquoImportant pharmacophoricfeatures of pan PPAR agonists common chemical feature analy-sis and virtual screeningrdquo European Journal of Medicinal Chem-istry vol 44 no 9 pp 3488ndash3495 2009

[170] S Sundriyal and P V Bharatam ldquolsquoSum of activitiesrsquo as depen-dent parameter a newCoMFA-based approach for the design ofpan PPAR agonistsrdquo European Journal of Medicinal Chemistryvol 44 no 1 pp 42ndash53 2009

[171] J Choi Y Park H S Lee Y Yang and S Yoon ldquo13-diphenyl-1H-pyrazole derivatives as a new series of potent PPAR120574 partialagonistsrdquo Bioorganic and Medicinal Chemistry vol 18 no 23pp 8315ndash8323 2010

[172] Z LWei P A Petukhov F Bizik et al ldquoIsoxazolyl-serine-basedagonists of peroxisome proliferator-activated receptor designsynthesis and effects on cardiomyocyte differentiationrdquo Journalof the American Chemical Society vol 126 no 51 pp 16714ndash16715 2004

[173] TKaya S CMohrD JWaxman and SVajda ldquoComputationalscreening of phthalate monoesters for binding to PPAR120574rdquoChemical Research in Toxicology vol 19 no 8 pp 999ndash10092006

[174] V G Maltarollo and K M Honorio ldquoMolecular properties offatty acids related to PPAR binding and metabolic diseasesrdquoMedicinal Chemistry Research pp 1ndash8 2012

[175] Y Ma S-Q Wang W-R Xu R-L Wang and K-C ChouldquoDesign novel dual agonists for treating type-2 diabetes bytargeting peroxisome proliferator-activated receptors with corehopping approachrdquo PloS ONE vol 7 no 6 Article ID e385462012

[176] L Michalik V Zoete G Krey et al ldquoCombined simulation andmutagenesis analyses reveal the involvement of key residues forperoxisome proliferator-activated receptor 120572 helix 12 dynamicbehaviorrdquo Journal of Biological Chemistry vol 282 no 13 pp9666ndash9677 2007

[177] J H Choi A S Banks J L Estall et al ldquoAnti-diabetic drugsinhibit obesity-linked phosphorylation of PPAR120574 3 by Cdk5rdquoNature vol 466 no 7305 pp 451ndash456 2010

[178] J H Choi A S Banks T M Kamenecka et al ldquoAntidiabeticactions of a non-agonist PPAR120574 ligand blocking Cdk5-mediat-ed phosphorylationrdquo Nature vol 477 pp 477ndash481 2011

[179] J Jyrkkarinne J Kablbeck J Pulkkinen et al ldquoMoleculardynamics simulations for humanCAR inverse agonistsrdquo Journal

of Chemical Information and Modeling vol 52 pp 457ndash4642012

[180] D Genest N Garnier A Arrault C Marot L Morin-Alloryand M Genest ldquoLigand-escape pathways from the ligand-binding domain of PPAR120574 receptor as probed by moleculardynamics simulationsrdquo European Biophysics Journal vol 37 no4 pp 369ndash379 2008

[181] V Zoete A Grosdidier andOMichielin ldquoPeroxisome prolifer-ator-activated receptor structures ligand specificity molecularswitch and interactions with regulatorsrdquo Biochimica et Biophys-ica Acta vol 1771 no 8 pp 915ndash925 2007

[182] G Pochetti NMitro A Lavecchia et al ldquoStructural insight intoperoxisome proliferator-activated receptor 120574 binding of twoureidofibrate-like enantiomers bymolecular dynamics cofactorinteraction analysis and site-directed mutagenesisrdquo Journal ofMedicinal Chemistry vol 53 no 11 pp 4354ndash4366 2010

[183] A Rogue C SpireM BrunNClaude andAGuillouzo ldquoGeneexpression changes induced by PPARgamma agonists in animaland human liverrdquo PPAR Research vol 2010 Article ID 32518316 pages 2010

[184] A Rogue M P Renaud N Claude A Guillouzo and C SpireldquoComparative gene expression profiles induced by PPAR120574 andPPAR120572120574 agonists in rat hepatocytesrdquo Toxicology and AppliedPharmacology vol 254 no 1 pp 18ndash31 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Research and TreatmentAIDS


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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Current treatment against Type 2 diabetes mellituslowast

Compounds Examples Mechanism Adverse effects

Secretagogues (sulfonylureasnonsulfonylureas) Glibenclamide meglitinide Increase of insulin secretion

Hypoglycaemiahyperinsulinaemia weight gainand vomiting

Biguanides Metformin Decrease of hepaticglucose output

Diarrhoea vomiting and lacticacidosis

120572-Glucosidase inhibitors Acarbose miglitol voglibose Inhibition of carbohydrateabsorption

Flatulence diarrhoea andabdominal pain

GLP1 GIP and DPP IV Exenatide LAF-237Liraglutide CJ-1131

Incretin effect improvement of120573-cell function Vomiting nausea

Thiazolidinediones Pioglitazone and Rosiglitazone PPAR120574 activation Weight gain oedemalowastModified from [2]

Section 2 The focus of this paper is to highlight the majorSAR and CADD studies performed on PPAR120574 Readersinterested in other targets are suggested to consult some of theexcellent recent and older reviews published on these topics[3ndash5] A brief literature search shows that a large amount ofwork has been done for the identification and testing of novelscaffolds for antidiabetic drug discovery in the PPAR arena Areview on PPAR120574 ligands was published with focus on dualpan and SPPARMs based strategy in 2008 [6] As discussedin the Section 32 a large number of crystal structure havebeen published for PPAR120574-ligand complexes but a thoroughunderstanding about the links between receptor-ligand inter-actions and antidiabetic benefits is far from completeThus anexpert perspective and overall assessment of these efforts areurgently required to give proper direction to these attempts

This paper begins with a brief introduction to currenttherapies for Type 2 diabetes followed by PPAR120574 localizationstructure and its ligands (natural and synthetic) This isfollowed by a brief classification of the ligands based on theiragonistic character Next in an attempt to fill the gaps inthe understanding of structure and function of PPAR120574 andits ligands this review is divided into sections on (i) SARstudies performed in the past twelve years An attempt hasbeenmade to present these studies in the chronological orderbut some exceptions are allowed to maintain connectivitybetween selected studies Majority of these studies involvedclassical medicinal chemistry approach to build SAR thatis to modify the substituents on a structural scaffold usingmostly biochemical intuition till the desired activityaffinityis observed (ii) Rational drug design approaches usingcomputational methods are then discussed In this sectionalso a chronological order has been followed with someexceptions and QSAR (2D 3D and higher-dimensionalmethods) pharmacophoremappingmolecular docking andstructure-based ligand based and de novo drug designapproaches employed are discussed

Despite the large number of SAR and CADD studiesreported on PPAR120574 agonists none of themolecules has madeit to the clinic after the introduction of TZDs Incompleteunderstanding of the dynamical nature of PPAR120574-ligandinteractions and translation of these interactions into phys-iological response could be one of the major reasons forthis failure Molecular dynamics simulation studies coupled

with other experimental techniques that have been utilizedby some groups to bridge these gaps are discussed brieflyRole of recently identified implications of phosphorylation ofPPAR120574 residues and resulting nonagonisticpartial agonisticcharacter of novel ligands is highlighted in the last section

2 Current Treatment Options forType 2 Diabetes

The cause of insulin resistance has been traced to defectsin insulin receptor (IR) function IR-signal transductionglucose transport and phosphorylation glycogen synthesisglucose oxidation and dysregulation of fatty acidmetabolism[7] Consequently these defects are targets of current phar-macological treatments as well as potential sites for newtherapies

Figure 1 shows the structures of currently marketed anda few withdrawn drugs which form the existing armoragainst Type 2 diabetes (see also Table 1) The biguanideslike metformin reduce the hepatic glucose production andalso enhance muscle insulin sensitivity Acarbose decreasesgastrointestinal absorption of carbohydrates by inhibiting 120572-glucosidase The sulfonylureas bind to specific receptors onthe 120573 cells of pancreas resulting in inhibition of K+ channelsleading to depolarization of cell membrane followed byexocytosis of insulin The dipeptidyl peptidase IV inhibitorsexert their antidiabetic effects by inhibiting the metabolismof glucagon-like peptide-1 (GLP-1) GLP-1 mediates its effectsthrough transmembrane GPC receptors leading to increasedinsulin secretion in response to feeding It has also beenshown to enhance the differentiation survival and matura-tion of the 120573 cells [8] This has encouraged the developmentof GLP-1 analogs also known as incretin mimetics likeexenatide a 39-amino acid peptide with glucoregulatoryproperties

Most of the above-mentioned drugmolecules act as director indirect insulin secretagogues of moderate to low poten-ciesThemajor cause of Type 2 diabetes a generalized insulinresistance in the body is actually not addressed by theselines of therapyThiazolidinediones (TZD) were identified in1995 to exert their antidiabetic actions by binding to PPAR120574with high affinity [9] This is the only class of molecules thatdecrease generalized insulin resistance in tissues like muscle


N

N

N

O O

N N

NN

NO

ON

N

N

N

NO

H

H

N

N

O





BMS

O

F

F

FN N

N N

F

F F



Sulfonylureas

OOS

O

O HN

HN

HN

HN

HN

HN

O

ClGlibenclamide

SO

ONH

NH

NH

NH

NH

NH

NH

O

Tolbutamide

N

OOS

O

O

O

Glimepiride

NN

O

SO

O

O

Glipizide

Metformin

N

Phenformin

Biguanides

Withdrawn

Thiazolidinediones

S

NHO

OO

N

N

Rosiglitazone (RGZ)

S

NHO

OON

Pioglitazone (PGZ)

S

NHO

OOOHO


OO

O

OH

OH

OHOH

HO

HO

HO

HO

HO

OO

NH

OH

OHOH

OHOH

HO

Acarbose


GLP-1 Analog


N N

H2N

H2N

H2N H2N

NH2

NH2

NH2

NH

NHNH2

NH2












1 101 166 244 468AB C D EF

1 72 137 215AB C D EF

441

1 110 175 251AB C D EF

477

DNA-binding domain



AF-1


AF-2

hPPAR120572

hPPAR120573

hPPAR1205741





Active sitevolume




2Q59 MRL20 (D) L 1407 A3



2Q5P MRL24 (G) L 1218 A3

2Q6S BVT13 (H) L 1568 A3








Table3Listof

PPAR120574

crystalstructuresd

epositedin

theP

DBdatabank

asof

2311

2012Re

solutio

nandprim

arycitatio

nfore

achstructurea

realso

given

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

1FM9

210

PPAR120574

2000

2-(2-BEN

ZOYL

-PHEN

YLAMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[22]

1GWX

250

PPAR120575

1999

2-(4-(3-[1-[2-(2-CH

LORO

-6-FLU

ORO

-PHEN

YL)-ET

HYL

]-3-(23-D

ICHLO

RO-

PHEN

YL)-URE

IDO]-PR

OPY

L)-PHEN

OXY

)-2-MET

HYL

-PRO

PIONIC

ACID

[23]

1I7G

220

PPAR120572

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1I7I

235

PPAR120574

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1K7L

250

PPAR120572

2001

2-(1-MET

HYL

-3-O

XO-3-PHEN

YL-PRO

PYLA

MIN

O)-3-(4-[2-(5-M

ETHYL

-2-

PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[25]

1KKQ

300

PPAR120572

2002

N-((2S)-2-(((1Z)-1-M

ETHYL

-3-O

XO-3-[4-(TRIFL

UORO

MET

HYL

)PH

ENYL

]PRO

P-1-E

NYL

)AMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-

YL)ETH

OXY

]PHEN

YL)PRO

PYL)PR

OPA

NAMID

E[26]

1KNU

250

PPAR120574

2002

(S)-3-(4-(2-CA

RBAZO

L-9-YL

-ETH

OXY

)-PH

ENYL

)-2-ET

HOXY

-PRO

PIONIC

ACID

[27]

1NYX

265

PPAR120574

2003

(2S)-2-ETH

OXY

-3-(4-[2-(10H-PHEN

OXAZIN-10-

YL)ETH

OXY

]PHEN

YL)PRO

PANOIC

ACID

[28]

1PRG

220

PPAR120574

1998

[16]

1WM0

290

PPAR120574

2004

2-[(24-DICHLO

ROBE

NZO

YL)A

MIN

O]-5-(PYR

IMID

IN-2-YLO

XY)BEN

ZOIC

ACID

[29]

1Y0S

265

PPAR120575

2000

(2S)-2-(4-[2-(3-[24-D

IFLU

ORO

PHEN

YL]-1-H

EPTY

LURE

IDO)ETH

YL]PHEN

OXY

)-2-MET

HYL

BUTY

RICAC

ID[30]

1ZEO

250

PPAR120574

2005

(2S)-(4-ISOPR

OPY

LPHEN

YL)[(2-M

ETHYL

-3-O

XO-57-DIPRO

PYL-23-DIH

YDRO

-12

-BEN

ZISO

XAZO

L-6-YL

)OXY

]ACE

TATE

[31]

1ZGY

180

PPAR120574

2005

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[32]

2ATH

228

PPAR120574

2005

2-(5-[3-(7-PRO

PYL-3-TR

IFLU

ORO

MET

HYL

BENZO

[D]ISO

XAZO

L-6-

YLOXY

)PRO

POXY

]INDOL-1-Y

L)ET

HANOIC

ACID

[33]

2AWH

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]

2B50

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2BAW

230

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[35]

2ENV

Solutio

nstructure

PPAR120575

Tobe

publish

edZINCIO

N

2F4B

207

PPAR120574

2006

(5-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

POXY

)-1H

-INDOL-1-

YL)A

CETICAC

ID[36]

2FVJ

199

PPAR120574

2006

GLY

CERO

L[37]

2G0G

254

PPAR120574

2006

3-FL

UORO

-N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-

YL]BEN

ZENES

ULF

ONAMID

E[38]

2G0H

230

PPAR120574

2006

N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-YL

]-35-

BIS(TR

IFLU

ORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[38]

2GTK

210

PPAR120574

2006

(2S)-3-(1-([2-(2-CH

LORO

PHEN

YL)-5-MET

HYL

-13-O

XAZO

L-4-YL

]MET

HYL

)-1H

-IN

DOL-5-YL

)-2-ET

HOXY

PROPA

NOIC

ACID

[39]

2GWX

230

PPAR120575

1999

[23]

2HFP

200

PPAR120574

2006

3-(4-M

ETHOXY

PHEN

YL)-N-(PH

ENYL

SULF

ONYL

)-1-[3-

(TRIFL

UORO

MET

HYL

)BEN

ZYL]-1H-INDOLE

-2-C

ARB

OXAMID

E[40]

2HWQ

197

PPAR120574

2006

[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-5-

YL)O

XY]A

CETICAC

ID[41]

2HWR

234

PPAR120574

2006

2-[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-4-

YL)O

XY]-2-MET

HYL

PROPA

NOIC

ACID

[41]

2I4J

210

PPAR120574

2007

(2R)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4P

210

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4Z

225

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2J14

280

PPAR120575

2006

(3-(4-[2-(24-DICHLO

RO-PHEN

OXY

)-ET

HYL

CARB

AMOYL

]-5-PH

ENYL

-ISOXAZO

L-3-YL

)-PH

ENYL

)-ACE

TICAC

ID[43]

2NPA

230

PPAR120572

2007

(2R3E

)-2-(4-[(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)MET

HOXY

]BEN

ZYL)-3-

(PRO

POXY

IMIN

O)BUTA

NOIC

ACID

[44]

2OM9

280

PPAR120574

2007

(6AR10AR)-3-(11-D

IMET

HYL

HEP

TYL)-1-HYD

ROXY

-66-D

IMET

HYL

-6A71010

A-TE

TRAHYD

RO-6H-BEN

ZO[C

]CHRO

MEN

E-9-CA

RBOXY

LICAC

ID[45]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2P4Y

225

PPAR120574

2008

(2R)-2-(4-CH

LORO

-3-([3-(6-MET

HOXY

-12-BEN

ZISO

XAZO

L-3-YL

)-2-MET

HYL

-6-

(TRIFL

UORO

MET

HOXY

)-1H

-INDOL-1-

YL]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[46]

2P54

179

PPAR120572

2007

2-MET

HYL

-2-(4-([((4-MET

HYL

-2-[4-(TRIFL

UORO

MET

HYL

)PHEN

YL]-13

-TH

IAZO

L-5-YL

)CARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[47]

2POB

230

PPAR120574

2007

N-[(2S)-2-[(2-BEN

ZOYL

PHEN

YL)A

MIN

O]-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-

OXAZO

L-4-YL

)ETH

OXY

]PHEN

YL)PRO

PYL]AC

ETAMID

E[48]

2PRG

230

PPAR120574

1998

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[16]

2Q59

220

PPAR120574

2007

(2S)-2-(2-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5G

270

PPAR120575

2007

[(7-([2-(3-M

ORP

HOLIN-4-YLP

ROP-1-Y

N-1-

YL)-6-([4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]ETH

YNYL

)PYR

IDIN

-4-YL]TH

IO)-23-DIH

YDRO

-1H

-INDEN

-4-YL)OXY

]ACE

TICAC

ID[50]

2Q5P

230

PPAR120574

2007

(2S)-2-(3-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5S

205

PPAR120574

2007

5-CH

LORO

-1-(4-C

HLO

ROBE

NZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q61

220

PPAR120574

2007

1-BEN

ZYL-5-CH

LORO

-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-C

ARB

OXY

LICAC

ID[49]

2Q6R

241

PPAR120574

2007

5-CH

LORO

-1-(3-M

ETHOXY

BENZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q6S

240

PPAR120574

2007

[49]

2Q8S

230

PPAR120574

2008

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(1H-

PYRR

OL-1-Y

L)PR

OPA

NOIC

ACID

[51]

2QMV

Solutio

nNMR

PPAR120574

Tobe

publish

ed

2REW

235

PPAR120572

Tobe

publish

edNN-BIS(3-D

-GLU

CONAMID

OPR

OPY

L)DEO

XYCH

OLA

MID

E

2VSR

205

PPAR120574

2008

(9S10E12Z)-9-H

YDRO

XYOCT

ADEC

A-1012

-DIENOIC

ACID

[52]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

N

N

O O

N N

NN

NO

ON

N

N

N

NO

H

H

N

N

O





BMS

O

F

F

FN N

N N

F

F F



Sulfonylureas

OOS

O

O HN

HN

HN

HN

HN

HN

O

ClGlibenclamide

SO

ONH

NH

NH

NH

NH

NH

NH

O

Tolbutamide

N

OOS

O

O

O

Glimepiride

NN

O

SO

O

O

Glipizide

Metformin

N

Phenformin

Biguanides

Withdrawn

Thiazolidinediones

S

NHO

OO

N

N

Rosiglitazone (RGZ)

S

NHO

OON

Pioglitazone (PGZ)

S

NHO

OOOHO


OO

O

OH

OH

OHOH

HO

HO

HO

HO

HO

OO

NH

OH

OHOH

OHOH

HO

Acarbose


GLP-1 Analog


N N

H2N

H2N

H2N H2N

NH2

NH2

NH2

NH

NHNH2

NH2












1 101 166 244 468AB C D EF

1 72 137 215AB C D EF

441

1 110 175 251AB C D EF

477

DNA-binding domain



AF-1


AF-2

hPPAR120572

hPPAR120573

hPPAR1205741





Active sitevolume




2Q59 MRL20 (D) L 1407 A3



2Q5P MRL24 (G) L 1218 A3

2Q6S BVT13 (H) L 1568 A3








Table3Listof

PPAR120574

crystalstructuresd

epositedin

theP

DBdatabank

asof

2311

2012Re

solutio

nandprim

arycitatio

nfore

achstructurea

realso

given

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

1FM9

210

PPAR120574

2000

2-(2-BEN

ZOYL

-PHEN

YLAMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[22]

1GWX

250

PPAR120575

1999

2-(4-(3-[1-[2-(2-CH

LORO

-6-FLU

ORO

-PHEN

YL)-ET

HYL

]-3-(23-D

ICHLO

RO-

PHEN

YL)-URE

IDO]-PR

OPY

L)-PHEN

OXY

)-2-MET

HYL

-PRO

PIONIC

ACID

[23]

1I7G

220

PPAR120572

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1I7I

235

PPAR120574

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1K7L

250

PPAR120572

2001

2-(1-MET

HYL

-3-O

XO-3-PHEN

YL-PRO

PYLA

MIN

O)-3-(4-[2-(5-M

ETHYL

-2-

PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[25]

1KKQ

300

PPAR120572

2002

N-((2S)-2-(((1Z)-1-M

ETHYL

-3-O

XO-3-[4-(TRIFL

UORO

MET

HYL

)PH

ENYL

]PRO

P-1-E

NYL

)AMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-

YL)ETH

OXY

]PHEN

YL)PRO

PYL)PR

OPA

NAMID

E[26]

1KNU

250

PPAR120574

2002

(S)-3-(4-(2-CA

RBAZO

L-9-YL

-ETH

OXY

)-PH

ENYL

)-2-ET

HOXY

-PRO

PIONIC

ACID

[27]

1NYX

265

PPAR120574

2003

(2S)-2-ETH

OXY

-3-(4-[2-(10H-PHEN

OXAZIN-10-

YL)ETH

OXY

]PHEN

YL)PRO

PANOIC

ACID

[28]

1PRG

220

PPAR120574

1998

[16]

1WM0

290

PPAR120574

2004

2-[(24-DICHLO

ROBE

NZO

YL)A

MIN

O]-5-(PYR

IMID

IN-2-YLO

XY)BEN

ZOIC

ACID

[29]

1Y0S

265

PPAR120575

2000

(2S)-2-(4-[2-(3-[24-D

IFLU

ORO

PHEN

YL]-1-H

EPTY

LURE

IDO)ETH

YL]PHEN

OXY

)-2-MET

HYL

BUTY

RICAC

ID[30]

1ZEO

250

PPAR120574

2005

(2S)-(4-ISOPR

OPY

LPHEN

YL)[(2-M

ETHYL

-3-O

XO-57-DIPRO

PYL-23-DIH

YDRO

-12

-BEN

ZISO

XAZO

L-6-YL

)OXY

]ACE

TATE

[31]

1ZGY

180

PPAR120574

2005

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[32]

2ATH

228

PPAR120574

2005

2-(5-[3-(7-PRO

PYL-3-TR

IFLU

ORO

MET

HYL

BENZO

[D]ISO

XAZO

L-6-

YLOXY

)PRO

POXY

]INDOL-1-Y

L)ET

HANOIC

ACID

[33]

2AWH

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]

2B50

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2BAW

230

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[35]

2ENV

Solutio

nstructure

PPAR120575

Tobe

publish

edZINCIO

N

2F4B

207

PPAR120574

2006

(5-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

POXY

)-1H

-INDOL-1-

YL)A

CETICAC

ID[36]

2FVJ

199

PPAR120574

2006

GLY

CERO

L[37]

2G0G

254

PPAR120574

2006

3-FL

UORO

-N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-

YL]BEN

ZENES

ULF

ONAMID

E[38]

2G0H

230

PPAR120574

2006

N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-YL

]-35-

BIS(TR

IFLU

ORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[38]

2GTK

210

PPAR120574

2006

(2S)-3-(1-([2-(2-CH

LORO

PHEN

YL)-5-MET

HYL

-13-O

XAZO

L-4-YL

]MET

HYL

)-1H

-IN

DOL-5-YL

)-2-ET

HOXY

PROPA

NOIC

ACID

[39]

2GWX

230

PPAR120575

1999

[23]

2HFP

200

PPAR120574

2006

3-(4-M

ETHOXY

PHEN

YL)-N-(PH

ENYL

SULF

ONYL

)-1-[3-

(TRIFL

UORO

MET

HYL

)BEN

ZYL]-1H-INDOLE

-2-C

ARB

OXAMID

E[40]

2HWQ

197

PPAR120574

2006

[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-5-

YL)O

XY]A

CETICAC

ID[41]

2HWR

234

PPAR120574

2006

2-[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-4-

YL)O

XY]-2-MET

HYL

PROPA

NOIC

ACID

[41]

2I4J

210

PPAR120574

2007

(2R)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4P

210

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4Z

225

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2J14

280

PPAR120575

2006

(3-(4-[2-(24-DICHLO

RO-PHEN

OXY

)-ET

HYL

CARB

AMOYL

]-5-PH

ENYL

-ISOXAZO

L-3-YL

)-PH

ENYL

)-ACE

TICAC

ID[43]

2NPA

230

PPAR120572

2007

(2R3E

)-2-(4-[(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)MET

HOXY

]BEN

ZYL)-3-

(PRO

POXY

IMIN

O)BUTA

NOIC

ACID

[44]

2OM9

280

PPAR120574

2007

(6AR10AR)-3-(11-D

IMET

HYL

HEP

TYL)-1-HYD

ROXY

-66-D

IMET

HYL

-6A71010

A-TE

TRAHYD

RO-6H-BEN

ZO[C

]CHRO

MEN

E-9-CA

RBOXY

LICAC

ID[45]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2P4Y

225

PPAR120574

2008

(2R)-2-(4-CH

LORO

-3-([3-(6-MET

HOXY

-12-BEN

ZISO

XAZO

L-3-YL

)-2-MET

HYL

-6-

(TRIFL

UORO

MET

HOXY

)-1H

-INDOL-1-

YL]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[46]

2P54

179

PPAR120572

2007

2-MET

HYL

-2-(4-([((4-MET

HYL

-2-[4-(TRIFL

UORO

MET

HYL

)PHEN

YL]-13

-TH

IAZO

L-5-YL

)CARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[47]

2POB

230

PPAR120574

2007

N-[(2S)-2-[(2-BEN

ZOYL

PHEN

YL)A

MIN

O]-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-

OXAZO

L-4-YL

)ETH

OXY

]PHEN

YL)PRO

PYL]AC

ETAMID

E[48]

2PRG

230

PPAR120574

1998

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[16]

2Q59

220

PPAR120574

2007

(2S)-2-(2-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5G

270

PPAR120575

2007

[(7-([2-(3-M

ORP

HOLIN-4-YLP

ROP-1-Y

N-1-

YL)-6-([4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]ETH

YNYL

)PYR

IDIN

-4-YL]TH

IO)-23-DIH

YDRO

-1H

-INDEN

-4-YL)OXY

]ACE

TICAC

ID[50]

2Q5P

230

PPAR120574

2007

(2S)-2-(3-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5S

205

PPAR120574

2007

5-CH

LORO

-1-(4-C

HLO

ROBE

NZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q61

220

PPAR120574

2007

1-BEN

ZYL-5-CH

LORO

-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-C

ARB

OXY

LICAC

ID[49]

2Q6R

241

PPAR120574

2007

5-CH

LORO

-1-(3-M

ETHOXY

BENZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q6S

240

PPAR120574

2007

[49]

2Q8S

230

PPAR120574

2008

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(1H-

PYRR

OL-1-Y

L)PR

OPA

NOIC

ACID

[51]

2QMV

Solutio

nNMR

PPAR120574

Tobe

publish

ed

2REW

235

PPAR120572

Tobe

publish

edNN-BIS(3-D

-GLU

CONAMID

OPR

OPY

L)DEO

XYCH

OLA

MID

E

2VSR

205

PPAR120574

2008

(9S10E12Z)-9-H

YDRO

XYOCT

ADEC

A-1012

-DIENOIC

ACID

[52]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























1 101 166 244 468AB C D EF

1 72 137 215AB C D EF

441

1 110 175 251AB C D EF

477

DNA-binding domain



AF-1


AF-2

hPPAR120572

hPPAR120573

hPPAR1205741





Active sitevolume




2Q59 MRL20 (D) L 1407 A3



2Q5P MRL24 (G) L 1218 A3

2Q6S BVT13 (H) L 1568 A3








Table3Listof

PPAR120574

crystalstructuresd

epositedin

theP

DBdatabank

asof

2311

2012Re

solutio

nandprim

arycitatio

nfore

achstructurea

realso

given

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

1FM9

210

PPAR120574

2000

2-(2-BEN

ZOYL

-PHEN

YLAMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[22]

1GWX

250

PPAR120575

1999

2-(4-(3-[1-[2-(2-CH

LORO

-6-FLU

ORO

-PHEN

YL)-ET

HYL

]-3-(23-D

ICHLO

RO-

PHEN

YL)-URE

IDO]-PR

OPY

L)-PHEN

OXY

)-2-MET

HYL

-PRO

PIONIC

ACID

[23]

1I7G

220

PPAR120572

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1I7I

235

PPAR120574

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1K7L

250

PPAR120572

2001

2-(1-MET

HYL

-3-O

XO-3-PHEN

YL-PRO

PYLA

MIN

O)-3-(4-[2-(5-M

ETHYL

-2-

PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[25]

1KKQ

300

PPAR120572

2002

N-((2S)-2-(((1Z)-1-M

ETHYL

-3-O

XO-3-[4-(TRIFL

UORO

MET

HYL

)PH

ENYL

]PRO

P-1-E

NYL

)AMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-

YL)ETH

OXY

]PHEN

YL)PRO

PYL)PR

OPA

NAMID

E[26]

1KNU

250

PPAR120574

2002

(S)-3-(4-(2-CA

RBAZO

L-9-YL

-ETH

OXY

)-PH

ENYL

)-2-ET

HOXY

-PRO

PIONIC

ACID

[27]

1NYX

265

PPAR120574

2003

(2S)-2-ETH

OXY

-3-(4-[2-(10H-PHEN

OXAZIN-10-

YL)ETH

OXY

]PHEN

YL)PRO

PANOIC

ACID

[28]

1PRG

220

PPAR120574

1998

[16]

1WM0

290

PPAR120574

2004

2-[(24-DICHLO

ROBE

NZO

YL)A

MIN

O]-5-(PYR

IMID

IN-2-YLO

XY)BEN

ZOIC

ACID

[29]

1Y0S

265

PPAR120575

2000

(2S)-2-(4-[2-(3-[24-D

IFLU

ORO

PHEN

YL]-1-H

EPTY

LURE

IDO)ETH

YL]PHEN

OXY

)-2-MET

HYL

BUTY

RICAC

ID[30]

1ZEO

250

PPAR120574

2005

(2S)-(4-ISOPR

OPY

LPHEN

YL)[(2-M

ETHYL

-3-O

XO-57-DIPRO

PYL-23-DIH

YDRO

-12

-BEN

ZISO

XAZO

L-6-YL

)OXY

]ACE

TATE

[31]

1ZGY

180

PPAR120574

2005

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[32]

2ATH

228

PPAR120574

2005

2-(5-[3-(7-PRO

PYL-3-TR

IFLU

ORO

MET

HYL

BENZO

[D]ISO

XAZO

L-6-

YLOXY

)PRO

POXY

]INDOL-1-Y

L)ET

HANOIC

ACID

[33]

2AWH

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]

2B50

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2BAW

230

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[35]

2ENV

Solutio

nstructure

PPAR120575

Tobe

publish

edZINCIO

N

2F4B

207

PPAR120574

2006

(5-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

POXY

)-1H

-INDOL-1-

YL)A

CETICAC

ID[36]

2FVJ

199

PPAR120574

2006

GLY

CERO

L[37]

2G0G

254

PPAR120574

2006

3-FL

UORO

-N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-

YL]BEN

ZENES

ULF

ONAMID

E[38]

2G0H

230

PPAR120574

2006

N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-YL

]-35-

BIS(TR

IFLU

ORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[38]

2GTK

210

PPAR120574

2006

(2S)-3-(1-([2-(2-CH

LORO

PHEN

YL)-5-MET

HYL

-13-O

XAZO

L-4-YL

]MET

HYL

)-1H

-IN

DOL-5-YL

)-2-ET

HOXY

PROPA

NOIC

ACID

[39]

2GWX

230

PPAR120575

1999

[23]

2HFP

200

PPAR120574

2006

3-(4-M

ETHOXY

PHEN

YL)-N-(PH

ENYL

SULF

ONYL

)-1-[3-

(TRIFL

UORO

MET

HYL

)BEN

ZYL]-1H-INDOLE

-2-C

ARB

OXAMID

E[40]

2HWQ

197

PPAR120574

2006

[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-5-

YL)O

XY]A

CETICAC

ID[41]

2HWR

234

PPAR120574

2006

2-[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-4-

YL)O

XY]-2-MET

HYL

PROPA

NOIC

ACID

[41]

2I4J

210

PPAR120574

2007

(2R)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4P

210

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4Z

225

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2J14

280

PPAR120575

2006

(3-(4-[2-(24-DICHLO

RO-PHEN

OXY

)-ET

HYL

CARB

AMOYL

]-5-PH

ENYL

-ISOXAZO

L-3-YL

)-PH

ENYL

)-ACE

TICAC

ID[43]

2NPA

230

PPAR120572

2007

(2R3E

)-2-(4-[(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)MET

HOXY

]BEN

ZYL)-3-

(PRO

POXY

IMIN

O)BUTA

NOIC

ACID

[44]

2OM9

280

PPAR120574

2007

(6AR10AR)-3-(11-D

IMET

HYL

HEP

TYL)-1-HYD

ROXY

-66-D

IMET

HYL

-6A71010

A-TE

TRAHYD

RO-6H-BEN

ZO[C

]CHRO

MEN

E-9-CA

RBOXY

LICAC

ID[45]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2P4Y

225

PPAR120574

2008

(2R)-2-(4-CH

LORO

-3-([3-(6-MET

HOXY

-12-BEN

ZISO

XAZO

L-3-YL

)-2-MET

HYL

-6-

(TRIFL

UORO

MET

HOXY

)-1H

-INDOL-1-

YL]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[46]

2P54

179

PPAR120572

2007

2-MET

HYL

-2-(4-([((4-MET

HYL

-2-[4-(TRIFL

UORO

MET

HYL

)PHEN

YL]-13

-TH

IAZO

L-5-YL

)CARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[47]

2POB

230

PPAR120574

2007

N-[(2S)-2-[(2-BEN

ZOYL

PHEN

YL)A

MIN

O]-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-

OXAZO

L-4-YL

)ETH

OXY

]PHEN

YL)PRO

PYL]AC

ETAMID

E[48]

2PRG

230

PPAR120574

1998

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[16]

2Q59

220

PPAR120574

2007

(2S)-2-(2-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5G

270

PPAR120575

2007

[(7-([2-(3-M

ORP

HOLIN-4-YLP

ROP-1-Y

N-1-

YL)-6-([4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]ETH

YNYL

)PYR

IDIN

-4-YL]TH

IO)-23-DIH

YDRO

-1H

-INDEN

-4-YL)OXY

]ACE

TICAC

ID[50]

2Q5P

230

PPAR120574

2007

(2S)-2-(3-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5S

205

PPAR120574

2007

5-CH

LORO

-1-(4-C

HLO

ROBE

NZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q61

220

PPAR120574

2007

1-BEN

ZYL-5-CH

LORO

-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-C

ARB

OXY

LICAC

ID[49]

2Q6R

241

PPAR120574

2007

5-CH

LORO

-1-(3-M

ETHOXY

BENZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q6S

240

PPAR120574

2007

[49]

2Q8S

230

PPAR120574

2008

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(1H-

PYRR

OL-1-Y

L)PR

OPA

NOIC

ACID

[51]

2QMV

Solutio

nNMR

PPAR120574

Tobe

publish

ed

2REW

235

PPAR120572

Tobe

publish

edNN-BIS(3-D

-GLU

CONAMID

OPR

OPY

L)DEO

XYCH

OLA

MID

E

2VSR

205

PPAR120574

2008

(9S10E12Z)-9-H

YDRO

XYOCT

ADEC

A-1012

-DIENOIC

ACID

[52]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Listof

PPAR120574

crystalstructuresd

epositedin

theP

DBdatabank

asof

2311

2012Re

solutio

nandprim

arycitatio

nfore

achstructurea

realso

given

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

1FM9

210

PPAR120574

2000

2-(2-BEN

ZOYL

-PHEN

YLAMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[22]

1GWX

250

PPAR120575

1999

2-(4-(3-[1-[2-(2-CH

LORO

-6-FLU

ORO

-PHEN

YL)-ET

HYL

]-3-(23-D

ICHLO

RO-

PHEN

YL)-URE

IDO]-PR

OPY

L)-PHEN

OXY

)-2-MET

HYL

-PRO

PIONIC

ACID

[23]

1I7G

220

PPAR120572

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1I7I

235

PPAR120574

2001

(2S)-2-ETH

OXY

-3-[4-(2-(4-

[(MET

HYL

SULF

ONYL

)OXY

]PHEN

YL)ETH

OXY

)PHEN

YL]PRO

PANOIC

ACID

[24]

1K7L

250

PPAR120572

2001

2-(1-MET

HYL

-3-O

XO-3-PHEN

YL-PRO

PYLA

MIN

O)-3-(4-[2-(5-M

ETHYL

-2-

PHEN

YL-O

XAZO

L-4-YL

)-ET

HOXY

]-PH

ENYL

)-PR

OPIONIC

ACID

[25]

1KKQ

300

PPAR120572

2002

N-((2S)-2-(((1Z)-1-M

ETHYL

-3-O

XO-3-[4-(TRIFL

UORO

MET

HYL

)PH

ENYL

]PRO

P-1-E

NYL

)AMIN

O)-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-

YL)ETH

OXY

]PHEN

YL)PRO

PYL)PR

OPA

NAMID

E[26]

1KNU

250

PPAR120574

2002

(S)-3-(4-(2-CA

RBAZO

L-9-YL

-ETH

OXY

)-PH

ENYL

)-2-ET

HOXY

-PRO

PIONIC

ACID

[27]

1NYX

265

PPAR120574

2003

(2S)-2-ETH

OXY

-3-(4-[2-(10H-PHEN

OXAZIN-10-

YL)ETH

OXY

]PHEN

YL)PRO

PANOIC

ACID

[28]

1PRG

220

PPAR120574

1998

[16]

1WM0

290

PPAR120574

2004

2-[(24-DICHLO

ROBE

NZO

YL)A

MIN

O]-5-(PYR

IMID

IN-2-YLO

XY)BEN

ZOIC

ACID

[29]

1Y0S

265

PPAR120575

2000

(2S)-2-(4-[2-(3-[24-D

IFLU

ORO

PHEN

YL]-1-H

EPTY

LURE

IDO)ETH

YL]PHEN

OXY

)-2-MET

HYL

BUTY

RICAC

ID[30]

1ZEO

250

PPAR120574

2005

(2S)-(4-ISOPR

OPY

LPHEN

YL)[(2-M

ETHYL

-3-O

XO-57-DIPRO

PYL-23-DIH

YDRO

-12

-BEN

ZISO

XAZO

L-6-YL

)OXY

]ACE

TATE

[31]

1ZGY

180

PPAR120574

2005

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[32]

2ATH

228

PPAR120574

2005

2-(5-[3-(7-PRO

PYL-3-TR

IFLU

ORO

MET

HYL

BENZO

[D]ISO

XAZO

L-6-

YLOXY

)PRO

POXY

]INDOL-1-Y

L)ET

HANOIC

ACID

[33]

2AWH

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]

2B50

200

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[34]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2BAW

230

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[35]

2ENV

Solutio

nstructure

PPAR120575

Tobe

publish

edZINCIO

N

2F4B

207

PPAR120574

2006

(5-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

POXY

)-1H

-INDOL-1-

YL)A

CETICAC

ID[36]

2FVJ

199

PPAR120574

2006

GLY

CERO

L[37]

2G0G

254

PPAR120574

2006

3-FL

UORO

-N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-

YL]BEN

ZENES

ULF

ONAMID

E[38]

2G0H

230

PPAR120574

2006

N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-YL

]-35-

BIS(TR

IFLU

ORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[38]

2GTK

210

PPAR120574

2006

(2S)-3-(1-([2-(2-CH

LORO

PHEN

YL)-5-MET

HYL

-13-O

XAZO

L-4-YL

]MET

HYL

)-1H

-IN

DOL-5-YL

)-2-ET

HOXY

PROPA

NOIC

ACID

[39]

2GWX

230

PPAR120575

1999

[23]

2HFP

200

PPAR120574

2006

3-(4-M

ETHOXY

PHEN

YL)-N-(PH

ENYL

SULF

ONYL

)-1-[3-

(TRIFL

UORO

MET

HYL

)BEN

ZYL]-1H-INDOLE

-2-C

ARB

OXAMID

E[40]

2HWQ

197

PPAR120574

2006

[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-5-

YL)O

XY]A

CETICAC

ID[41]

2HWR

234

PPAR120574

2006

2-[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-4-

YL)O

XY]-2-MET

HYL

PROPA

NOIC

ACID

[41]

2I4J

210

PPAR120574

2007

(2R)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4P

210

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4Z

225

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2J14

280

PPAR120575

2006

(3-(4-[2-(24-DICHLO

RO-PHEN

OXY

)-ET

HYL

CARB

AMOYL

]-5-PH

ENYL

-ISOXAZO

L-3-YL

)-PH

ENYL

)-ACE

TICAC

ID[43]

2NPA

230

PPAR120572

2007

(2R3E

)-2-(4-[(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)MET

HOXY

]BEN

ZYL)-3-

(PRO

POXY

IMIN

O)BUTA

NOIC

ACID

[44]

2OM9

280

PPAR120574

2007

(6AR10AR)-3-(11-D

IMET

HYL

HEP

TYL)-1-HYD

ROXY

-66-D

IMET

HYL

-6A71010

A-TE

TRAHYD

RO-6H-BEN

ZO[C

]CHRO

MEN

E-9-CA

RBOXY

LICAC

ID[45]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2P4Y

225

PPAR120574

2008

(2R)-2-(4-CH

LORO

-3-([3-(6-MET

HOXY

-12-BEN

ZISO

XAZO

L-3-YL

)-2-MET

HYL

-6-

(TRIFL

UORO

MET

HOXY

)-1H

-INDOL-1-

YL]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[46]

2P54

179

PPAR120572

2007

2-MET

HYL

-2-(4-([((4-MET

HYL

-2-[4-(TRIFL

UORO

MET

HYL

)PHEN

YL]-13

-TH

IAZO

L-5-YL

)CARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[47]

2POB

230

PPAR120574

2007

N-[(2S)-2-[(2-BEN

ZOYL

PHEN

YL)A

MIN

O]-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-

OXAZO

L-4-YL

)ETH

OXY

]PHEN

YL)PRO

PYL]AC

ETAMID

E[48]

2PRG

230

PPAR120574

1998

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[16]

2Q59

220

PPAR120574

2007

(2S)-2-(2-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5G

270

PPAR120575

2007

[(7-([2-(3-M

ORP

HOLIN-4-YLP

ROP-1-Y

N-1-

YL)-6-([4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]ETH

YNYL

)PYR

IDIN

-4-YL]TH

IO)-23-DIH

YDRO

-1H

-INDEN

-4-YL)OXY

]ACE

TICAC

ID[50]

2Q5P

230

PPAR120574

2007

(2S)-2-(3-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5S

205

PPAR120574

2007

5-CH

LORO

-1-(4-C

HLO

ROBE

NZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q61

220

PPAR120574

2007

1-BEN

ZYL-5-CH

LORO

-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-C

ARB

OXY

LICAC

ID[49]

2Q6R

241

PPAR120574

2007

5-CH

LORO

-1-(3-M

ETHOXY

BENZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q6S

240

PPAR120574

2007

[49]

2Q8S

230

PPAR120574

2008

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(1H-

PYRR

OL-1-Y

L)PR

OPA

NOIC

ACID

[51]

2QMV

Solutio

nNMR

PPAR120574

Tobe

publish

ed

2REW

235

PPAR120572

Tobe

publish

edNN-BIS(3-D

-GLU

CONAMID

OPR

OPY

L)DEO

XYCH

OLA

MID

E

2VSR

205

PPAR120574

2008

(9S10E12Z)-9-H

YDRO

XYOCT

ADEC

A-1012

-DIENOIC

ACID

[52]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2BAW

230

PPAR120575

2006

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[35]

2ENV

Solutio

nstructure

PPAR120575

Tobe

publish

edZINCIO

N

2F4B

207

PPAR120574

2006

(5-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

POXY

)-1H

-INDOL-1-

YL)A

CETICAC

ID[36]

2FVJ

199

PPAR120574

2006

GLY

CERO

L[37]

2G0G

254

PPAR120574

2006

3-FL

UORO

-N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-

YL]BEN

ZENES

ULF

ONAMID

E[38]

2G0H

230

PPAR120574

2006

N-[1-(4-FL

UORO

PHEN

YL)-3-(2-THIENYL

)-1H

-PYR

AZO

L-5-YL

]-35-

BIS(TR

IFLU

ORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[38]

2GTK

210

PPAR120574

2006

(2S)-3-(1-([2-(2-CH

LORO

PHEN

YL)-5-MET

HYL

-13-O

XAZO

L-4-YL

]MET

HYL

)-1H

-IN

DOL-5-YL

)-2-ET

HOXY

PROPA

NOIC

ACID

[39]

2GWX

230

PPAR120575

1999

[23]

2HFP

200

PPAR120574

2006

3-(4-M

ETHOXY

PHEN

YL)-N-(PH

ENYL

SULF

ONYL

)-1-[3-

(TRIFL

UORO

MET

HYL

)BEN

ZYL]-1H-INDOLE

-2-C

ARB

OXAMID

E[40]

2HWQ

197

PPAR120574

2006

[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-5-

YL)O

XY]A

CETICAC

ID[41]

2HWR

234

PPAR120574

2006

2-[(1-(3-[(6-BE

NZO

YL-1-

PROPY

L-2-NAPH

THYL

)OXY

]PRO

PYL)-1H-INDOL-4-

YL)O

XY]-2-MET

HYL

PROPA

NOIC

ACID

[41]

2I4J

210

PPAR120574

2007

(2R)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4P

210

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2I4Z

225

PPAR120574

2007

(2S)-2-(4-(2-[13

-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

BUTA

NOIC

ACID

[42]

2J14

280

PPAR120575

2006

(3-(4-[2-(24-DICHLO

RO-PHEN

OXY

)-ET

HYL

CARB

AMOYL

]-5-PH

ENYL

-ISOXAZO

L-3-YL

)-PH

ENYL

)-ACE

TICAC

ID[43]

2NPA

230

PPAR120572

2007

(2R3E

)-2-(4-[(5-M

ETHYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)MET

HOXY

]BEN

ZYL)-3-

(PRO

POXY

IMIN

O)BUTA

NOIC

ACID

[44]

2OM9

280

PPAR120574

2007

(6AR10AR)-3-(11-D

IMET

HYL

HEP

TYL)-1-HYD

ROXY

-66-D

IMET

HYL

-6A71010

A-TE

TRAHYD

RO-6H-BEN

ZO[C

]CHRO

MEN

E-9-CA

RBOXY

LICAC

ID[45]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2P4Y

225

PPAR120574

2008

(2R)-2-(4-CH

LORO

-3-([3-(6-MET

HOXY

-12-BEN

ZISO

XAZO

L-3-YL

)-2-MET

HYL

-6-

(TRIFL

UORO

MET

HOXY

)-1H

-INDOL-1-

YL]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[46]

2P54

179

PPAR120572

2007

2-MET

HYL

-2-(4-([((4-MET

HYL

-2-[4-(TRIFL

UORO

MET

HYL

)PHEN

YL]-13

-TH

IAZO

L-5-YL

)CARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[47]

2POB

230

PPAR120574

2007

N-[(2S)-2-[(2-BEN

ZOYL

PHEN

YL)A

MIN

O]-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-

OXAZO

L-4-YL

)ETH

OXY

]PHEN

YL)PRO

PYL]AC

ETAMID

E[48]

2PRG

230

PPAR120574

1998

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[16]

2Q59

220

PPAR120574

2007

(2S)-2-(2-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5G

270

PPAR120575

2007

[(7-([2-(3-M

ORP

HOLIN-4-YLP

ROP-1-Y

N-1-

YL)-6-([4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]ETH

YNYL

)PYR

IDIN

-4-YL]TH

IO)-23-DIH

YDRO

-1H

-INDEN

-4-YL)OXY

]ACE

TICAC

ID[50]

2Q5P

230

PPAR120574

2007

(2S)-2-(3-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5S

205

PPAR120574

2007

5-CH

LORO

-1-(4-C

HLO

ROBE

NZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q61

220

PPAR120574

2007

1-BEN

ZYL-5-CH

LORO

-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-C

ARB

OXY

LICAC

ID[49]

2Q6R

241

PPAR120574

2007

5-CH

LORO

-1-(3-M

ETHOXY

BENZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q6S

240

PPAR120574

2007

[49]

2Q8S

230

PPAR120574

2008

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(1H-

PYRR

OL-1-Y

L)PR

OPA

NOIC

ACID

[51]

2QMV

Solutio

nNMR

PPAR120574

Tobe

publish

ed

2REW

235

PPAR120572

Tobe

publish

edNN-BIS(3-D

-GLU

CONAMID

OPR

OPY

L)DEO

XYCH

OLA

MID

E

2VSR

205

PPAR120574

2008

(9S10E12Z)-9-H

YDRO

XYOCT

ADEC

A-1012

-DIENOIC

ACID

[52]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2P4Y

225

PPAR120574

2008

(2R)-2-(4-CH

LORO

-3-([3-(6-MET

HOXY

-12-BEN

ZISO

XAZO

L-3-YL

)-2-MET

HYL

-6-

(TRIFL

UORO

MET

HOXY

)-1H

-INDOL-1-

YL]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[46]

2P54

179

PPAR120572

2007

2-MET

HYL

-2-(4-([((4-MET

HYL

-2-[4-(TRIFL

UORO

MET

HYL

)PHEN

YL]-13

-TH

IAZO

L-5-YL

)CARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

OXY

)PRO

PANOIC

ACID

[47]

2POB

230

PPAR120574

2007

N-[(2S)-2-[(2-BEN

ZOYL

PHEN

YL)A

MIN

O]-3-(4-[2-(5-M

ETHYL

-2-PHEN

YL-13-

OXAZO

L-4-YL

)ETH

OXY

]PHEN

YL)PRO

PYL]AC

ETAMID

E[48]

2PRG

230

PPAR120574

1998

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[16]

2Q59

220

PPAR120574

2007

(2S)-2-(2-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5G

270

PPAR120575

2007

[(7-([2-(3-M

ORP

HOLIN-4-YLP

ROP-1-Y

N-1-

YL)-6-([4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]ETH

YNYL

)PYR

IDIN

-4-YL]TH

IO)-23-DIH

YDRO

-1H

-INDEN

-4-YL)OXY

]ACE

TICAC

ID[50]

2Q5P

230

PPAR120574

2007

(2S)-2-(3-([1-(4-MET

HOXY

BENZO

YL)-2-MET

HYL

-5-(TR

IFLU

ORO

MET

HOXY

)-1H

-IN

DOL-3-YL

]MET

HYL

)PHEN

OXY

)PRO

PANOIC

ACID

[49]

2Q5S

205

PPAR120574

2007

5-CH

LORO

-1-(4-C

HLO

ROBE

NZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q61

220

PPAR120574

2007

1-BEN

ZYL-5-CH

LORO

-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-C

ARB

OXY

LICAC

ID[49]

2Q6R

241

PPAR120574

2007

5-CH

LORO

-1-(3-M

ETHOXY

BENZY

L)-3-(PH

ENYL

THIO

)-1H

-INDOLE

-2-

CARB

OXY

LICAC

ID[49]

2Q6S

240

PPAR120574

2007

[49]

2Q8S

230

PPAR120574

2008

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(1H-

PYRR

OL-1-Y

L)PR

OPA

NOIC

ACID

[51]

2QMV

Solutio

nNMR

PPAR120574

Tobe

publish

ed

2REW

235

PPAR120572

Tobe

publish

edNN-BIS(3-D

-GLU

CONAMID

OPR

OPY

L)DEO

XYCH

OLA

MID

E

2VSR

205

PPAR120574

2008

(9S10E12Z)-9-H

YDRO

XYOCT

ADEC

A-1012

-DIENOIC

ACID

[52]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

2VST

235

PPAR120574

2008

(9Z11E13S)-13-HYD

ROXY

OCT

ADEC

A-91

1-DIENOIC

ACID

[52]

2VV0

255

PPAR120574

2008

DOCO

SA-471013

1619

-HEX

AEN

OIC

ACID

[52]

2VV1

220

PPAR120574

2008

(4S5E

7Z10Z13Z16Z19Z)-4-H

YDRO

XYDOCO

SA-571013

1619

-HEX

AEN

OIC

ACID

[52]

2VV2

275

PPAR120574

2008

(5R6E

8Z11Z14Z17Z)-5-H

YDRO

XYIC

OSA

-681114

17-PEN

TAEN

OIC

ACID

[52]

2VV3

285

PPAR120574

2008

(6E10Z13Z16Z19Z)-4-O

XODOCO

SA-610

1316

19-PEN

TAEN

OIC

ACID

[52]

2VV4

235

PPAR120574

2008

(8R9Z

12Z)-8-H

YDRO

XY-6-O

XOOCT

ADEC

A-91

2-DIENOIC

ACID

[52]

2XKW

202

PPAR120574

Tobe

publish

ed(5R)-5-(4-[2-(5-ET

HYL

PYRIDIN

-2-YL)ET

HOXY

]BEN

ZYL)-13-THIAZO

LIDIN

E-24-

DIO

NE

2XYJ

230

PPAR120575

2011

PENTA

ETHYL

ENEGLY

COL

[53]

2XYW

314

PPAR120575

2011

3-CH

LORO

-6-FLU

ORO

-N-[2-[4-[(5-PRO

PAN-2-YL-13

4-THIADIAZO

L-2-

YL)SULFAMOYL

]PHEN

YL]ETH

YL]-1-B

ENZO

THIO

PHEN

E-2-CA

RBOXAMID

E[53]

2XYX

270

PPAR120575

2011

B-OCT

YLGLU

COSIDE

[53]

2YFE

200

PPAR120574

2012

AMORF

RUTIN1

[54]

2ZK0

236

PPAR120574

2009

[55]

2ZK1

261

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[55]

2ZK2

226

PPAR120574

2009

GLU

TATH

IONE

[55]

2ZK3

258

PPAR120574

2009

(5E11E14E)-8-O

XOIC

OSA

-591114

-TET

RAEN

OIC

ACID

[55]

2ZK4

257

PPAR120574

2009

(5E8E

11Z13E)-15-OXO

ICOSA

-581113

-TET

RAEN

OIC

ACID

[55]

2ZK5

245

PPAR120574

2009

3-[5-(2-NITRO

PENT-1-E

N-1-

YL)FURA

N-2-YL]BE

NZO

ICAC

ID[55]

2ZK6

241

PPAR120574

2010

DIFLU

ORO

(5-(2-[(5-OCT

YL-1H-PYR

ROL-2-YL

-KAPP

AN)M

ETHYL

IDEN

E]-2H-

PYRR

OL-5-YL

-KAPP

AN)PEN

TANOAT

O)BORO

N[56]

2ZNN

201

PPAR 120572

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNO

240

PPAR120574

2009

(2S)-2-(4-PR

OPO

XY-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)BEN

ZYL)BU

TANOIC

ACID

[57]

2ZNP

300

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[57]

2ZNQ

265

PPAR120575

2009

(2S)-2-(3-[(([2-FL

UORO

-4-

(TRIFL

UORO

MET

HYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]-4-

MET

HOXY

BENZY

L)BU

TANOIC

ACID

[57]

2ZVT

190

PPAR120574

2009

(5E14E)-11-O

XOPR

OST

A-591

214-TET

RAEN

-1-OIC

ACID

[58]

3ADS

225

PPAR120574

2010

INDOMET

HAC

IN[56]

3ADT

270

PPAR120574

2010

(5-H

YDRO

XY-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADU

277

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ADV

227

PPAR120574

2010

SERO

TONIN

[56]

3ADW

207

PPAR120574

2010

(5-M

ETHOXY

-1H-INDOL-3-YL

)ACE

TICAC

ID[56]

3ADX

195

PPAR120574

2010

INDOMET

HAC

IN[56]

3AN3

230

PPAR120574

2011

(2S)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3AN4

230

PPAR120574

2011

(2R)-2-BEN

ZYL-3-(4-PRO

POXY

-3-([((4-[(3S5S7S)-TRICY

CLO[3311sim37sim

]DEC

-1-YL

]PHEN

YL)C

ARB

ONYL

)AMIN

O]M

ETHYL

)PHEN

YL)PRO

PANOIC

ACID

[59]

3B0Q

210

PPAR120574

Tobe

publish

ed(5S)-5-((6-[(2-FLU

ORO

BENZY

L)OXY

]NAPH

THALE

N-2-YL)MET

HYL

)-13

-TH

IAZO

LIDIN

E-24-DIO

NE

3B0R

215

PPAR120574

Tobe

publish

ed2-CH

LORO

-5-N

ITRO

-N-PHEN

YLBE

NZA

MID

E

3B1M

160

PPAR120574

2011

(9AS)-8-ACE

TYL-N-[(2-ETH

YLNAPH

THALE

N-1-YL

)MET

HYL

]-17-D

IHYD

ROXY

-3-

MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[60]

3B3K

260

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3BC5

227

PPAR120574

2009

(5-(3-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]BEN

ZYL)-2-

PHEN

YL-2H-123-TRIAZO

L-4-YL

)ACE

TICAC

ID[62]

3CDP

280

PPAR120574

Tobe

publish

ed(2S)-2-(4-CH

LORO

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

3CDS

265

PPAR120574

2008

(2S)-2-(4-ET

HYL

PHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3CS8

230

PPAR120574

2008

24-TH

IAZO

LIDIINED

IONE

5-[[4-[2-(MET

HYL

-2-PYR

IDIN

YLAMIN

O)ETH

OXY

]PHEN

YL]M

ETHYL

]-(9CL

)[63]

3CWD

240

PPAR120574

2008

(9E12Z)-10-NITRO

OCT

ADEC

A-91

2-DIENOIC

ACID

[64]

3D5F

220

PPAR120575

Tobe

publish

ed(4-[3-(4-ACE

TYL-3-HYD

ROXY

-2-

PROPY

LPHEN

OXY

)PRO

POXY

]PHEN

OXY

)ACE

TICAC

ID3D

6D240

PPAR120574

2008

(2S)-2-(BIPH

ENYL

-4-YLO

XY)-3-PH

ENYL

PROPA

NOIC

ACID

[61]

3DY6

290

PPAR120575

2008

2-(([3-(34-DIH

YDRO

ISOQUIN

OLIN-2(1H)-

YLSU

LFONYL

)PHEN

YL]C

ARB

ONYL

)AMIN

O)BEN

ZOIC

ACID

[65]

3ET0

240

PPAR120574

2009

SS-(2-H

YDRO

XYET

HYL

)THIO

CYST

EINE

[66]

3ET1

250

PPAR120572

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3ET2

224

PPAR120575

2009

1-BUTA

NOL

[66]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3ET3

195

PPAR120574

2009

3-(5-M

ETHOXY

-1-[(4-MET

HOXY

PHEN

YL)SULF

ONYL

]-1H

-INDOL-3-

YL)PRO

PANOIC

ACID

[66]

3FEI

240

PPAR120572

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FEJ

201

PPAR120574

2009

(2S)-3-(4-([2-(4-C

HLO

ROPH

ENYL

)-13

-THIAZO

L-4-YL

]MET

HOXY

)-2-

MET

HYL

PHEN

YL)-2-ET

HOXY

PROPA

NOIC

ACID

[67]

3FUR

230

PPAR120574

2009

CHLO

RIDEIO

N[68]

3G8I

220

PPAR120572

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3G9E

230

PPAR120574

2009

(2S)-2-M

ETHOXY

-3-(4-[2-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)ETH

OXY

]-1-

BENZO

THIO

PHEN

-7-YL)PR

OPA

NOIC

ACID

[69]

3GBK

230

PPAR120574

2009

2-[(1-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

PYL)-1234-

TETR

AHYD

ROQUIN

OLIN-5-YL)OXY

]-2-MET

HYL

PROPA

NOIC

ACID

[70]

3GWX

240

PPAR120575

1999

581114

17-EIC

OSA

PENTA

ENOIC

ACID

[23]

3GZ9

200

PPAR120575

2009

HEP

TYL-BE

TA-D

-GLU

COPY

RANOSIDE

[71]

3HO0

260

PPAR120574

2009

(2S)-2-(4-PH

ENET

HYL

PHEN

OXY

)-3-PH

ENYL

-PRO

PANOIC

ACID

[72]

3HOD

210

PPAR120574

2009

(2S)-2-(4-BE

NZY

LPHEN

OXY

)-3-PH

ENYL

PROPA

NOIC

ACID

[72]

3IA6

231

PPAR120574

2009

(2S)-3-(4-[3-(5-MET

HYL

-2-PHEN

YL-13-O

XAZO

L-4-YL

)PRO

PYL]PH

ENYL

)-2-(2H-

123-TRIAZO

L-2-YL

)PRO

PANOIC

ACID

[73]

3K8S

255

PPAR120574

2008

2-CH

LORO

-N-(3-CH

LORO

-4-[(5-C

HLO

RO-13-BEN

ZOTH

IAZO

L-2-

YL)SULFANYL

]PHEN

YL)-4-(TRIFL

UORO

MET

HYL

)BEN

ZENES

ULF

ONAMID

E[74]

3KDT

270

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-(MET

HOXY

CARB

ONYL

)GLY

CINE

[75]

3KDU

207

PPAR120572

2010

N-(3-([2-(4-C

HLO

ROPH

ENYL

)-5-MET

HYL

-13-O

XAZO

L-4-

YL]M

ETHOXY

)BEN

ZYL)-N

-[(4-M

ETHYL

PHEN

OXY

)CARB

ONYL

]GLY

CINE

[75]

3KMG

210

PPAR120574

Tobe

publish

ed41015840-[(23-D

IMET

HYL

-5-([(1S)-1-P

HEN

YLPR

OPY

L]CA

RBAMOYL

)-1H

-INDOL-1-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID

3LMP

190

PPAR120574

2010

(9AS)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-N-(1-

NAPH

THYL

MET

HYL

)-9-OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[76]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3NOA

198

PPAR120574

Tobe

publish

ed(5-(3-[4-(BIPH

ENYL

-4-YLC

ARB

ONYL

)-2-PR

OPY

LPHEN

OXY

]PRO

POXY

)-1H

-IN

DOL-1-Y

L)AC

ETIC

ACID

3OSI

270

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OSW

255

PPAR120574

2011

S-12

-PRO

PANED

IOL

[77]

3OZ0

300

PPAR120575

2011

[4-(((1S)-1-[(24-D

ICHLO

ROPH

ENYL

)CARB

AMOYL

]-13

-DIH

YDRO

-2H-ISO

INDOL-

2-YL

)MET

HYL

)-2-MET

HYL

PHEN

OXY

]ACE

TICAC

ID[78]

3PBA

230

PPAR120574

2011

26-DIBRO

MO-4-[2-(35-D

IBRO

MO-4-H

YDRO

XYPH

ENYL

)PRO

PAN-2-YL]PH

ENYL

HYD

ROGEN

SULFAT

E[79]

3PEQ

240

PPAR120575

2011

[(4-(BUTY

L[2-MET

HYL

-41015840

-(MET

HYL

SULFANYL

)BIPHEN

YL-3-

YL]SULFAMOYL

)NAPH

THALE

N-1-

YL)O

XY]A

CETICAC

ID[80]

3PRG

290

PPAR120574

1998

[81]

3QT0

250

PPAR120574

Tobe

publish

ed

11-(4-D

IMET

HYL

AMIN

O-PHEN

YL)-17-H

YDRO

XY-13-MET

HYL

-17-PR

OP-1-Y

NYL

-12

6781112

1314

1516

17-D

ODEC

AHYD

RO-C

YCLO

PENTA

[A]PHEN

ANTH

REN-3-O

NE

3R5N

200

PPAR120574

2011

551015840-D

I(PR

OP-2-EN

-1-YL

)BIPHEN

YL-221015840

-DIO

L[82]

3R8A

241

PPAR120574

2011

2-ET

HYL

-57-DIM

ETHYL

-3-((1S)-5-[2-(1H-TET

RAZO

L-5-YL

)PHEN

YL]-23-

DIH

YDRO

-1H-INDEN

-1-YL

)-3H

-IMID

AZO

[45-B]PYR

IDIN

E[83]

3R8I

230

PPAR120574

2011

2-(4-(2-[13-BEN

ZOXAZO

L-2-YL

(HEP

TYL)AMIN

O]ETH

YL)PHEN

OXY

)-2-

MET

HYL

PROPA

NOIC

ACID

[84]

3SP6

221

PPAR120572

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3SP9

230

PPAR120575

Tobe

publish

ed(5E)-5-[(3AS4R

5R6A

S)-5-H

YDRO

XY-4-[(1E3S4R)-3-H

YDRO

XY-4-M

ETHYL

OCT

-1-E

N-6-YN-1-

YL]H

EXAHYD

ROPE

NTA

LEN-2(1H)-YL

IDEN

E]PE

NTA

NOIC

ACID

3S9S

255

PPAR120574

2011

1-(34-DICHLO

ROBE

NZY

L)-2-M

ETHYL

-N-[(1R)-1-

PHEN

YLPR

OPY

L]-1H-

BENZIMID

AZO

LE-5-C

ARB

OXAMID

E[85]

3SZ1

230

PPAR120574

2012

NONANOIC

ACID

[86]

3TY0

200

PPAR120574

2011

(5R)-5-(3-([3-(6-M

ETHOXY

-12-BEN

ZOXAZO

L-3-YL

)-2-OXO

-23-D

IHYD

RO-1H-

BENZIMID

AZO

L-1-Y

L]MET

HYL

)PHEN

YL)-5-MET

HYL

-13-O

XAZO

LIDIN

E-24-

DIO

NE

[87]

3T03

210

PPAR120574

2012

(5Z)-5-(5-BR

OMO-2-M

ETHOXY

BENZY

LIDEN

E)-3-(4-MET

HYL

BENZY

L)-13-

THIAZO

LIDIN

E-24-DIO

NE

[88]


Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table3Con

tinued

PDBID

Resolutio

nProtein

Year

Ligand

name

Reference

3U9Q

152

PPAR120574

2012

DEC

ANOIC

ACID

[89]

3V9T

165

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(3-ETH

OXY

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-D

IHYD

ROXY

-3-MET

HOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

CARB

OXAMID

E[90]

3V9V

160

PPAR120574

2011

MET

HYL

3-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-

OXO

-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)PR

OPA

NOAT

E[90]

3VJH

220

PPAR120574

2012

(2S)-2-[4-MET

HOXY

-3-([[4-

(TRIFL

UORO

MET

HYL

)BEN

ZOYL

]AMIN

O]M

ETHYL

)BEN

ZYL]PE

NTA

NOIC

ACID

[91]

3VJI

261

PPAR120574

2012

(2S)-2-4-BU

TOXY

-3-[(4-[(3S5S7S)-T

RICY

CLO[3311sim37sim

]DEC

-1-YL

]BEN

ZOYLA

MIN

O)M

ETHYL

]BEN

ZYLBU

TANOIC

ACID

[91]

3V9Y

210

PPAR120574

2012

4-(4-[(([(9A

S)-8-ACE

TYL-17-D

IHYD

ROXY

-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-

99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-

YL]C

ARB

ONYL

)AMIN

O)M

ETHYL

]NAPH

THALE

N-2-YL)BU

TANOIC

ACID

[90]

3VN2

218

PPAR120574

2012

41015840-[(171015840

-DIM

ETHYL

-21015840

-PRO

PYL-1H

31015840

H-251015840

-BIBEN

ZIMID

AZO

L-31015840-

YL)M

ETHYL

]BIPHEN

YL-2-C

ARB

OXY

LICAC

ID[92]

4PRG

290

PPAR120574

1999

(+minus)(2S5S)-3-(4-(4-C

ARB

OXY

PHEN

YL)BUTY

L)-2-H

EPTY

L-4-OXO

-5-

THIAZO

LIDIN

E[93]

4A4V

200

PPAR120574

Tobe

publish

edAMORF

RUTIN2

4A4W

200

PPAR120574

Tobe

publish

edAMORF

RUTINB

4F9M

190

PPAR120574

2012

(9AS)-8-ACE

TYL-N-[(2-ETH

YL-4-FLU

ORO

NAPH

THALE

N-1-

YL)M

ETHYL

]-17-

DIH

YDRO

XY-3-M

ETHOXY

-9A-

MET

HYL

-9-O

XO-99A-

DIH

YDRO

DIBEN

ZO[BD]FURA

N-4-C

ARB

OXAMID

E


N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N N OS

NH

O

O

Hydrophobic tail

Acidic head

Linker


(a) (b) (c) (d)

(e) (f) (g) (h)



acid

RGZ

PPAR120574

Zn finger motif

PPRE(DNA)





Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Linolenic acid (1)

O OH



O

OH

OH

OH

OHHO


O


OO

OOH



S

O

O

ON


SNH

O

O

OOHO


SNH

O

O

O


O

HO

O

N

OF

FF

OO

MRL20 (10)

O NH

NH

O

OO


SNH NH

O

O

ONN













SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























SNH

O

O

ON

N

O


SNH

O

O

ON

N PAT5A (13)

N

N

O

OO

OO

PA-082 (14)

OOH

O

NN

O

NHCl

Cl

Cl

Cl

SHN HO

SN

S

Cl

O

O

T2384 (16)

O

O

O

NNH O

Farglitazar (17)

BVT13 (15)

CF3


O

OHOH

OON

O

Ragaglitazar (20)

O

OHOH

SO

O

NO

Aleglitazar (18)

O OH

O

ONS

LYS10929 (21)

O

O

OSO

O

O

Tesaglitazar (19)

ONO

ON OO

O

Muraglitazar (22)



O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O OH

HNO

O

Fmoc-L-leucine (23)

O O

O

F

FF

Cl

HN

O

Metaglidasen (24)

N

HN

HN

SOO

O

Cl

Cl

FK614 (25)

O

OH

N

NN

N

Telmisartan (26)


OO

O

O

BADGE (27)

O

NH

O

Cl

GW9662 (28)

N+∙Ominus










O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

BnO

NO NHS

O


N

ON O

HOOC

N

O

O HN

O

O

O OH

O


OCH2CH3

HOOC OCH2CH3














S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















S

HN O

OO

N N

NR


S

HN

OO

O

N N

RGZ (6)

S

HN

OO

O

ON




S

HN OO

O

N N

RGZ (6)

S

HN OO

ON

DRF2189 (36)

SNH

O

O

O

N

N

OPMT13 (38)

O NH

O

O

O

O

N

OO








SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















SNH

O

OOO

O

S

NHO

O

OO

O


PPAR120572120574 dual (40)


S

HN O

OO

N N

RGZ (6)

S

HN OO

O

N NO

S

HN O

OO

N N

S

HN OO

O

N N

O

SNH

O

O

O

N

N

N

N

N

R





SNH

O

O

ONN

N N

RO








O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

OH OH

OH

OO

Cl

OOO

N

O

OON


F3C

F3C



(48)



O COOH


O COOH

Cl

COOH

Cl


O






N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

OH

O

OO

O

N OHO

O

O

O

N OH

O

O

O

O4

5

PPAR120572120574120575 PAN agonist (52)





NH

O X

COOH

OEtCOOH

OEt

OH



HO

HO

HO

ON

O


ON

O

ON

HN

O





N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

NO O

COOH

O

N

O

O

COOH

O

HN






50(from trans-





O

O

OOCl

O

F

OOH

O

Cyclize

O

OOH

OH







COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















COOHCOOH

O

NH

O


O

NH

O


(R)(S)

(a)

COOH

O

NH

O

NH

O

N

N

N

FF


(R)

(b)





















NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























NHX

O

O

OOn

OOH

O

N

Cl

F

OHN

Cl

Cl

GW2433

HNC

X

O

O

R

Cl

N

O

N

COOH

O


R1




SO

ONH

N

O

OO

NH

NH

O

Gliquidone (67)

OHO

HN

O

NO

O

SOO

NH

X

O

Nateglinide (68)


(a)

R OH

O

R O

O

SNH

O

O

RS

N

O

O

R

RS

O O

NH

O

RS

O O

N

O

pKasim48

pKasim5

pKasim65⊖

(b)


















O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























O NH

HN

COOH

O

Cl

O

OHO

O

O

O

O

OH

OH

(733)

O

N

NS

OH

O

O

(744)

NN

O

O

O

Cl

SP3300 (75)

SN

S

O

OO

SP1818 (76)


NO2



NH

OHN

O

OO


O

OHO

R

R




50





O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

NH

O O N

O

GW409544

O

NH

HOHO O

N O N

NHO

Comp 1

























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























Abbreviations








Acknowledgments


References










































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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