the importance of synthetic drugs for type 2 diabetes drug discovery - expert opin. drug discov....

8/17/2019 The Importance of Synthetic Drugs for Type 2 Diabetes Drug Discovery - Expert Opin. Drug Discov. (2013) 8(11)13…

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1. Introduction

2. Pathophysiology of T2DM

3. Overview of current synthetic

drugs in the treatment of

T2DM

4. New synthetic compounds as

DPP-4 inh ibi tors

5. New synthetic compounds as

SGLT2 inhibitors

7. Conclusion

8. Expert opinion

Review

The importance of synthet ic drugs

for t ype 2 diabetes drug discoveryMaliheh Safavi, AlirezaForoumadi & Mohammad Abdollahi††T ehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceuti cal Sciences

Research Center, T ehran, I ran

Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic,

multi-causal and heterogeneous disorder which causes significant morbid-

ity and mo rtality wit h considerable burden to healthcare resources. The

number of deaths due t o T2DM highlights the insufficiency of the cur-

rently available drugs for controlling the disease and its complications

and more needs to be done.

Areas covered: This paper reviews the updated pathobiology of T2DM that

shoul d be t argeted in drug discovery. Furt her, the arti cle provides discussion

on t he mechanism of action, side eff ects and stru ctu re of t he current ly avail-

able synthetic drugs. The aut hors specif ically evaluate tw o newer classes of

anti-di abetic agent s: di pepti dyl pept idase IV (DPP-4) and sodiu m-glucose

transpor ter-2 (SGLT2). They also present in formation on new er synthet ic com-pounds. The article also highlig hts the key int eraction s betw een synthetic

compounds and DPP-4 acti ve site residues for ratio nal drug design.

Expert opin ion : Numerous ant i-hyperglycaemic drugs are currently available

but many are limited b y their adverse effects. The identi fication of the 3D

stru ctu re of DPP-4 has opened n ew avenues fo r design, t hus aiming t o p ro-

duce drugs that directly exploit the structural characteristics of this binding

site. Further, structural- and ligand-based screening techniques have been

developed fo r designi ng novel DPP-4 and SGLT2 i nhib ito rs. There has also

been progress wi th t he design and development of novel T2DM therapeut ics

includin g: PPARa/ dual agon ists, Sir tu in 1 activators, glycogen p hosphorylase

inhibit ors and prot ein tyrosine phosphatase 1B inhibi tors. Finding new tar-

gets and synth esis methods is sti ll essential but it is becoming accepted that

no diabeti c th erapy is ‘best suit ed’ wit h each patient respond ing dif ferent ly.

Keywords: antidiabeti ca!ents, di"e"tidyl "e"tidase I # inhibitors, sodium!lucosetrans"orter

$ i nhibitors, syntheticdru!s, ty"e$ diabetes

%"ert '"in( )ru!)iscov( *$+-. 8*./--0-1-

1. Introduction

)iabetes com"rises a !rou" of metaboli c disorders characterised by chronichy"er!lycaemia2ith disorders in themetabolism of carbohydrate, fat and "roteinthat result in defects in secretion and action of insulin 34( )ysfunction andfailureof various or!ans, es"ecially theeyes, 5i dneys, nerves, heart andthebloodvessels aretheusual com"licati ons of diabetes 3$,-4( )iabetes is mainly divided into four mainty"es i ncludin! insulinde"endent diabetes mellitus *ty"e ., noni nsulinde"endent diabetes mellitus *ty"e$., !estati onal diabetes and other s"ecificty"es 3,64(

T y"e$ diabetes mellitus *T $)M. is very common andaccounts for ~ 0+--078of all diabeticcases( T he2orld2ideincreasein T $)M becomes amost im"ortanthealth concern 374( T $)M is usually accom"anied2ith insulin resistancein thes5eletal muscles and the liver, and the reduction in insuli n "roduction by the "ancreas 314( 9enetic susce"ti bility and various environmental factors 3:,;4 are alsoinvolved in T $)M( Patients 2ith T $)M are at ris5 of vascular com"lications

10.1517/17460441.2013.837883 © 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X 1339All rights reserved: reproduction in whole or in part not permitted


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such as coronary artery disease, stro5e, hy"ertension,ne"hro"athy, "eri"heral vascular disease, neuro"athy and

reti no"athy 30-4( I t has been su!!ested that hi!her !lucoselevels may be a ris5 factor for dementia 364( Althou!hT $)M 2as traditionally seen in individuals over the a!eof6+, recent data from several countries confi rm that T $)Moccurs in youn!er "eo"le even in childhood 37,14( Cases ofT $)M that occurs before-+ years of a!eusually develo"diabeti cne"hro"athy, renal failure, blindness andatheroscleroticvascular diseasein their -+s 3:4(

Althou!h thereareseveral thera"euti co"ti ons availablefor the mana!ement of diabetes, most of them r es"ond only intheshorttomedium term( Further, most of current thera"iesareassociated 2ith an increased ris5 of adverseeffects such as2ei!ht !ain *sul"honylureas, thiazoli dinediones and insulin.,

hy"o!lycaemia *sul"honylureas and insulin., !astrointesti nalintolerance *metformin. and myocardial infarction *rosi!litazone. 3;,04( Researchers are tryin! to fi nd thera"ies better than thethreeoldest classes, for eam"le, insulin, sul"honylureas and bi!uanides but the ne2er ones havenot sho2n more"otency and2ereoften less effectivei n lo2erin!!lycaemia304(

Alternativeto thesesyntheti ca!ents, ne2insulin analo!ues,inhaled insuli n and many medicinal "lants arebein!investi !ated for "ossiblebenefits in diabetes 3$+-+4( Moreover, insuli n--mimeti ccom"lees havebeen synthesized in thethou!htthat these com"lees affect both diabetes and its com"lications 3-,-$4( 'f course, concerns of safety and tolerability ofcurrent treatments and the "ro!ressivenatureof T $)M callfor ne2classes of medicines( T his revie2"rovides adiscussionof current syntheti c"harmacolo!ical a!ents andne2syntheti ccom"ounds for T $)M(

2. Pathophysiology of T2DM

Unli5esim"lecharacterisation of ty"e diabetes, the"atho!enesis of T $)M is morecom"le and sti ll remains amatter of ar!ument( T hemost "roblemis that thes"ecifi caetiolo!ies

have not yet been clearly elucidated( For instance, unli5ety"e diabetes, autoimmune destruction of cells does notoccur and 5etoacidosis seldom occurs 3--4( As mentioned earlier, "eri"heral insuli n resistance and bcell dysfunction arerather involved in T $)M 3-64( Insulin resistance and therelated conse


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5inaseC( T hesearethe5ey si!nallin!molecules in theactivation of !lucoseu"ta5e, inhibition of a"o"tosis and synthesisof "roteins 360,7$764(

I t is thou!ht that i n adi"oseandretinal tissues, "hos"horylation on s"ecific serine sites *Ser-+:. on I RS reduces

the tyrosine "hos"horylation of the insulin rece"tor 36;,774(T hecyto5ineT Fa "lays ama@or rolethrou!h "hos"horylation of theIRS "rotein on Ser-+: site( T Fainducedinhibition of I RS si!nallin!can reduceA5t "hos"horylationand sto" the insuli n si!nallin! "ath2ay 3-0,6;4( Also, it hasbeen sho2n that T Fa causes mar5ed do2nre!ulati on ofthe adi"ocytes and muscle cells insulinre!ulable !lucosetrans"orter 3714(

Accordin!to recent studies, thecirculatin!I? 1 correlates2ith insulin sensiti vity in obese humans 37:4( T his meansthat both T F a and I?1 and other adi"ocytes"ecifi csi!nallin! elements such as resistin and le"tin can alter insuli nsensitivity by "rovo5in! diverse 5ey ste"s in the "rocess ofinsulin action 3-1,7;4( Any defect in i nsulin action or theIRS

tri!!ers bcells in a2ay to cause T $)M 3704( T heinter"laybet2een insulin resistance and bcell dysfunction remainshi!hly com"le 31+4( Studies of i nsulinresistant animals i llustrate an im"ortant rolefor e"ansion of thebcell mass andenhanced bcell function as the com"ensatory mechanisms 314( In most obese and insulinresistant individuals,bcell com"ensati on reduces dueto hy"er!lycaemiaand li"idtoicity 31$,1-4( Continuous declineof bcell function usually

ends u" in bcell ehaustion and finally bcell failure anddiabetes 31+4(

umerous studies have demonstrated that enhanced "roinflammatorycyto5ines, freeradicals andoidativestress arecentral events to thedevelo"ment of diabeti ccom"lications3-,16114(

)ominant causeof oidativestress in diabetes is !lucoseautoidation that leads to "roduction of free radicals 31:4( 'idativestress causes bcell death viainduction of mitochondrial stressdurin!develo"ment of diabetes( In "ancreaticb cells, im"ortanttar!ets for an oidant insult are AT Pde"endent "otassium*BAT P. channels and cell metabolism 31;4( T heefficacies of different a""roaches in thereductionof diabetesinducedoidativestress have been studied and usa!e of antioidants as thesu""lement to dru! re!imen of T $)M "atients has beenrecommended310:04( riefly, the"athobiolo!y of T $)M 2hichareconsidered as tar!ets for classicand current syntheticdru!saresummarisedin Figure1(

3. Overview of current synthetic drugs in thetreatment of T2DM

3.1 Biguanides

T heclass of bi!uanides includes themetformin andt2o2ithdra2n a!ents "henformin and buformin( T he reason for removin! "henformin and buformin from the mar5et 2asthe occurrence of fatal lactic acidosis 3;+,;4( I ntroduced inthe mar5et in 07+, metformin is a 2ellacce"ted fi rstl ine

Insulinresistance Thiazolidinedionesbiguanides

Biguanides

Sulphonylureasnon-

sulphonylureasGLP-1 analogsDPP4 inhibitors

Sulphonylureas

β celldysfunction

(decreased insulinsecretion)

Decreasedglucose

transport (muscleand adipose tissue)

Increasedhepatic glucose

production

Impairedglucose

tolerance

Obesity & lifestyle Genes

Type 2diabete

mellitus

Figure 1. Pathobiology and targets for current drugs in T2DM.

Importance of synthetic drugs for T2DM drug discovery

Expert Opin. Drug Discov. (2013) 8(11) 1341


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choicefor the treatment of T $) M dueto its !ood efficacy,lo2 "riceandlo2rateof adverseeffects es"ecially in lon!termuse3;$;74( Metformin reduces fasti n!"lasma!lucoseconcentrations by reducin! rates of he"atic !lucose"roduction throu!ha reduction in !luconeo!enesis and !lyco!enolysis 3;1;;4(Metformin also affects "eri"herally and im"roves s5eletal myocyte !lucose u"ta5e, reduces theoverall "lasmafree fatty acid*FFA. concentration and induces mild 2ei!ht loss throu!hreduction of caloricinta5e3;0,0+4(

Acti vation of adenosine mono"hos"hateacti vated "rotein5inase*AMPB. is r e o2ever, !astrointesti nalintolerance, such as nausea, abdominal "ain and diarrhoea,

ha""ens as asideeffect in about -+8 of theusers that l imitsthe com"liance of "atients to consume to" effectivedoses 306,074( Althou!h rare, fatal lactic acidosis mi!ht beobserved in someusers 301,0:4 and thus i t should not beusedin "atients 2ith liver disease 3074, renal dysfuncti on 30:4 andin those2ith asli!ht de!reeof creati nineelevation 30;4( T hestructure of bi!uanide*red hi!hli !ht in metformin structurein Table 1. is conventionally re"resented in a 2ron! tautomericform2hich 2as correctedin $++7 3004( T hey aremoderately stron!bases andform > Cl salts


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T a b l e 1 . C u r r e n t a n t i - d i a b e t i c s y n t h e t i c d r u g c l a s s e s .

D r u g c l a s s

D r u g s t r u c t u r e

M e c h a n i s m

o f a c t i o n

S i d e e f f e c t s

S t u d y

B i g u a n i d e

N

N

N H 2

C H 3

C H 3 N

H 2

N H

M e t f o r m i n

R e d u c e s h e p a t i c g l u c o s e

p r o d u c t i o n , i n c r e a s e s

p e r i p h e r a l g l u c o s e u t i l i s

a t i o n

a n d i n s u l i n s e n s i t i v i t y

G a s t r o i n t e s t i n a l c o m p l a i n t s

a n d l a c t i c a c i d o s i s

B h a r a t a m e t a l . 2 0 0 5 ,

L i p s k a e t a l . 2 0 1 1 [ 9 9 , 2 3 6 ]

S u l p h o n y l u r e a s

S

O

O

H N

NH HN

N O

O

O

G l i m e p i r i d e

S t i m u l a t e s i n s u l i n r e l e a s e

f r o m p a n c r e a s a n d r e d u c e s

p o s t - a b s o r p t i v e r a t e s o f

e n d o g e n o u s g l u c o s e

p r o d u c t i o n

V e r y r a r e a d v e r s e e f f e c t s

c o m p a r e d t o o t h e r

s u l p h o n y l u r e a s s i d e e f f e c t s

s u c h a s h y p o g l y c a e m i a a n d

w e i g h t g a i n

K o r y t k o w s k i 2 0 0 4 ,

B e c

i c e t a l . 2 0 0 3 [ 1 0 7 , 2 3 7 ]

N o n - s u l p h o n y l u r e a s

O N H

H

H O

O

N a t e g l i n i d e

I n c r e a s e s i n s u l i n s e c r e t i o n i n

t h e p a n c r e a s

M i l d g a s t r o i n t e s t i n a l

c o m p l a i n t s a n d w e i g h t g a i n

C h a c h i n e t a l . 2 0 0 3 ,

C a m p b e l l 2 0 0 5 [ 1 1 9 , 1 2 0 ]

T h i a z o l i d i n e d i o n e s

H N

O

S

N H

O O

N

R o s i g l i t a z o n e

L o w e r s i n s u l i n r e s i s t a n c

e i n

p e r i p h e r a l t i s s u e b y

a c t i v a t i n g P P A R - g

W e i g h t g a i n , f l u i d r e t e n t i o n

a n d h e a r t f a i l u r e

Y k i - J a r v i n e n 2 0 0 4 ,

D e f r o n z o 2 0 0 9 [ 1 2 5 , 1 2 8 ]

D i s a c c h a r i d a s e i n h i b i t o r s

O O H O H

O

H

O

O O H

O H

O

H O

H O

O O H

H O

N H

H O

O H

H O

H O

H 3 C

A c a r b o s e

I n h i b i t s i n t e s t i n a l a -

g l u c o s i d a s e e n z y m e s

G a s t r o i n t e s t i n a l d i s t u r b a n c e

s u c h a s f l a t u l e n c e ,

a b d o m i n a l d i s t e n s i o n ,

s t o m a c h r u m b l e a n d

d i a r r h o e a

B a l f o u r e t a l . 1 9 9 3 ,

C l i s s o l d a n d E d w a r d s

1 9 8 8 [ 1 4 1 , 2 3 8 ]




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T a b l e 1 . C u r r e n t a n t i - d i a b e t i c s y n t h e t i c d r u g c l a s s e s ( c o n t i n

u e d ) .

D r u g c l a s s

D r u g s t r u c t u r e

M e c h a n i s m

o f a c t i o n

S i d e e f f e c t s

S t u d y

G L P 1 a g o n i s t s

T h r S e r A s p V a l S e r

G l u G l y G l n

A l a A l a

L y s

C O O H

O

N H

H

O

C H 3

G l u

P h e

I l e

A l a

T r p

L e u

V a l

A r g

G l y

A r g

G l y

S e r

L e u

T y r

P h e

T h r

G l y

G l u

A l a

H i s

L i r a g l u t i d e

S t i m u l a t e s i n s u l i n

b i o s y n t h e s i s a n d s e c r e t i o n ,

i n h i b i t s g l u c a g o n s e c r e t i o n

a n d s l o w s g a s t r i c e m p t y i n g

N a u s e a a n d v o m i t i n g

W a

j c b e r g a n d A m a r a h

2 0 1 0 , M a d s b a d

2 0 0 9 [ 1 5 9 , 2 3 9 ]

D P P - 4 i n h i b i t o r s

H N

O

N

O H

N

V i l d a g l i p t i n

I n h i b i t s D P P - 4 t h a t i m p r o v e s

g l y c a e m i c c o n t r o l

F e w g a s t r o i n t e s t i n a l

d i s t u r b a n c e

G u p t a e t a l . 2 0 0 9 ,

P a n

i n a 2 0 0 7 [ 1 6 8 , 2 4 0 ]

S G L 2 i n h i b i t o r s

O

O H

O H

O H

H O

C H 3

S

F

I n v o k a n a ( c a n a g l i f l o z i n )

I n h i b i t s S G L T 2 i n t h e k i d n e y s

L o w i n c i d e n c e o f

h y p o g l y c a e m i a a n d g e n i t a l

i n f e c t i o n s i n f e m a l e s

N o m u r a e t a l . 2 0 1 0 ,

R o s e n s t o c k e t a l .

2 0 1 2 [ 1 7 9 , 2 4 1 ]

D o p a m i n e - 2 a g o n i s t s

H N

N

B r

H H N

O

N

O O

N

H O

O

H

C H 3 S O 3 H

B r o m o c r i p t i n e

R e s e t s a b n o r m a l l y e l e v a

t e d

h y p o t h a l a m i c d r i v e f o r

i n c r e a s e d p l a s m a g l u c o s e ,

t r i g l y c e r i d e a n d F F A l e v

e l s

F a t i g u e , n a u s e a , v o m i t i n g ,

d i z z i n e s s a n d h e a d a c h e

K e c h e 2 0 1 0 ,

K u m a r e t a l .

2 0 1 2 [ 1 8 1 , 1 8 2 ]

M. Safavi et al.

1344 Expert Opin. Drug Discov. (2013) 8(11)


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3.4 Thiazolidinediones

T ro!litazone 2as the fi rst thiazolidinedione a""roved as a!lucoselo2eri n! thera"y for "atients 2ith T $)M in00: 30;,$4( T r o!litazone2as subse


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features andlar!er bindin!"oc5et of this rece"tor "rovidene2insi!hts into the molecular details of "e"tide li!and bindin!andamorereliablestr uctural tem"latefor thedesi!n of s"ecificand "otent small molecules for thetreatment of T $)M 37-4(

T heshort halflife*tE$ ~ --(7 min. of 9?P, becauseof their ra"id inactivation by di"e"tidyl "e"tidase I#*)PP6. in the circulation, is a ma@or difficulty for itsuse 360,764( %enatide is asynthetic form of eendin6 thatoccurs naturally in thesalivaof the9ilamonster *alar!evenomous lizard nativeto south2estern United States. and i tsamino acid se o2ever, at this time, the tolerance and safety "rofi le of)PP6 inhibitors are considered as ecellent( Possibleincreased ris5 of acute "ancreatitis in the short term andoccurrence of chronic "ancreatiti s in the lon!er term areamon! concerns attr ibuted to increase in 9?P levels(onconsistent results re!ardin! a "ossible effect of 9?Pand)PP6 inhibitors on theeocrine"ancreas 2erere"orted

in various animal models 3104( In vie2 of li 5ely toic sideeffects associated 2ith the inhibition of other members of)PP family *inhibition of 2hich 2as lin5edtotoicity in animal studies., it seems necessary to desi!n selecti veinhibitorstar!etin! )PP6 over )PP; and )PP0 3:+4( Achievin!desired selectivity to2ard theinhibition of )PP6 over other related "e"tidases such as )PP; and )PP0 and lon!acti n!"otential for maimal efficacy arethemain challen!es(

3.8 Sodium-glucose t ransport er-2 inhibitors

Cana!liflozin from the ne2 class of medications calledsodium!lucose trans"orter$ *S9?T $. inhibitors 2asa""roved by F )A in March $+- 3:4( Althou!h there are

several candidates, S9?T $ inhibitors such as da"a!lifl ozinand I+::- are no2 in various sta!es of clinical develo"ment, and the"hlorizine, ser!lifl ozin and remo!liflozin havebeen discarded 3:$4(

Bidney "lays a 5ey role in !lucosehomeostasis, "rimarilyby the r eabsor"tion of fi ltered !lucose es"ecially by theS9?T $ located in the"roimal convoluted tubule( S9?T ,theother S9?T s isoform, is the5ey trans"orter for !lucoseabsor"tion in the!astrointestinal tract and"lays only aminor role in the 5idney 3:-,:64( T he e"ression of S9?T $ andother renal !lucose trans"orters 2ere elevated in diabetic"atients 3:74( S9?T $ inhibitors, 2ith a!reater selectivity for S9? T $ versus S9? T , offer a considerable advanta!e as"otential antidiabeti c medications, because of their ability

to inhibit renal !lucosereabsor"tion and subse


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structure*!lucosiderin!i s hi!hli !hted in red in cana!liflozinstructurein theTable1.( Since, the'lin5a!eof thestructureof S9?T $ inhibitors is a metabolic tar!et for b!lucosidaseenzymes that can restrict the activity of S9?T $ inhibitorsin vivo, ne2er candidate 2ith aC!lucoside lin5a!e such ascana!liflozin have been synthesized 3:;4( Cana!lifl ozin as aC!lucoside bearin! a heteroaromati c rin! has im"rovedmetabolicstability in com"arison to '!lucoside3:04(

3.9 Bile acid sequestrants/dopamine-2 agonists

From this cate!ory, t2o classes of dru!s 2ere alreadya""roved for other diseases( Colesevelam hydrochloride is abile acid se


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NH2

N

O

HO

C

Saxagliptin [244,245]DPP-4 IC50: 26 nMDPP8/DPP4 > 400 foldDPP9/DPP4 > 75 fold

N

F

F

F

NH2 O

NN

N

CF3

Sitagliptin [243]DPP-4 IC50: 18 nMQPP IC50 > 100 μMDPP8 IC50: 48 μM

HN

O

N

OH

CN

Vildagliptin [246]DPP-4 IC50: 3.5 nMQPP IC50 > 500 μM

N

C

NH3+

TFA-N

CH3

O

CH3F

O

NO

CH3 CH3

1 [189]DPP-4 IC50: 0.025 μMQPP IC50 > 100 μMDPP-9 IC50 > 100 μMDPP-8 IC50 > 100 μM

NH3C

CH3

O N

CH3

NH3+

Cl-

O

F

2 [189]DPP-4 IC50: 0.016 μMDPP-8 IC50: 25 μMDPP-9 IC50 > 100 μM

F

F

F

N

NH2 O

N

N

CF3

CH3

H

F

3 [190]DPP-4 IC50: 0.0058 μMQPP IC50: 15 μMDPP-8 IC50: 46 μMDPP-9 IC50 > 100 μM

NCN

OHN

N

H

H

O

N

CH3

CH3

4 [191]DPP-4 IC50: 0.009 μMDPP-8 IC50: 17.38 μMDPP-9 IC50: 5.7 μM

N

CNHN

NH

O

CH3 CH3

O

N

N

N

CH3

HCl

5 [193]DPP-4 IC50: 3.8 nMDPP-8 IC50: 68 nMDPP-9 IC50: 60 nM

N

N

NH O

N

S

N

CF3

6 [194]DPP-4 IC50: 0.37 nMDPP-8 IC50: 72.4 nMDPP-9 IC50: 105 nM

N

S

ONH

N

N

N

N

CH3

7 [197]DPP-4 IC50: 0.37 nMDPP-8 IC50: 260 nMDPP-9 IC50: 540 nM

FF

F NH

NH2 O

N

NN

N

CF3

8 [163]

DPP-4 IC50: 0.031 μMDPP-8 IC50: 78.5 μMDPP-9 IC50: 41.6 μM

Figure 2. Schemati c representat ion of chemical structure of some examples of the pepti domimetic DPP-4.

M. Safavi et al.



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"e"tidases, )PP; and )PP0 30:4( T he 5ey interactions of

thevil da!li"tin and saa!li"tin structures 2ith )PP6 activesiteresidues are"resented in Table2(

oshidaet al( desi!ned novel "yrroli dinederivati ves 2ithout electro"hilicnitrilemoiety focused on the substituent atthe g"ositi on of "roline moiety of "rolylthiazolidine corestructure to2ards increasin! theaffi nity to theS$ subsiteof)PP6 306,0;,004( Accordin!to"revious re"orts, introducin!an electrondefi cient 6aryl"i"erazineresults in hi!hly "otent

and lon!lastin! inhibitors 3$++4( Fused bicyclic heteroaryl"i

"erazinesubsti tuted at theg"osition of the"rolinestructurein theinvesti!ation of ? "rolylthiazoli dines lac5i n!theelectro"hil ic nitrile 2as "reviously e"lored( Com"ound *6.*$trifluoro 100 μMDPP-9 IC50 > 100 μM

N

NN

N

O

O

CH3

N

N

N

NH2CH3

Linagliptin [247]DPP-4 IC50: 1 nMQPP IC50 > 100 μMDPP-8 IC50: 40 μMDPP-9 IC50 > 10 μM

F

F

F N

NH3+TFA-

NN

N O

9 [201]DPP-4 IC50: 1.2 nMQPP IC50: > 100 μMDPP-8 IC50 > 100 μMDPP-9 IC50 > 19 μM

N

N N

N

O

H

N

NH2

NN

10 [203]DPP-4 IC50: 0.001 μMDPP-4 inhib. in rat: 80%Muscarinicreceptor M1 IC50: 1.190 μM

N

NN

NH2

Cl

Cl

11 [204]DPP-4 Ki: 0.006 μmDPP-8 Ki: > 30 μMDPP-9 Ki: > 30 μM

NH2

H

N

F

F

O

N

CH3

CH3

CH3

O2S

12 [206]DPP-4 IC50: 0.055 μMQPP IC50: 63 μMDPP-8 IC50 > 100 μM

DPP-9 IC50 > 100 μM

F

F NH

NH2

N

CO2NH2

13 [206]DPP-4 IC50: 0.018 μM

QPP IC50: 22 μMDPP-8 IC50: 18 μMDPP-9 IC50: 27 μM

CH3

N

NNH2

H3C CH3

HNO

O

14 [207]DPP-4 IC50: 1.3 nM

QPPIC50: 20 μMDPP-8 IC50 > 60 μMDPP-9 IC50 > 60 μM

N

O

N

N

N

NH2C

Cl

F

O

OH

CH3

15 [208]DPP-4 IC50: 0.48 nM

QPP IC50 > 10 μMDPP-8 IC50 > 100 μMDPP-9 IC50 > 100 μM

Figure 3. Schematic representati on o f chemical structure of some examples of t he non -peptidomimet ic DPP-4 inhibi to rs.




12/25

Table 2. Key interactions betw een inhi bit or structures and DPP-4 acti ve site residues.

DPP-4 i nh ibi tor In vol ved inh ib it or st ru ct ure Int eract io n t yp e DPP-4 resi du e St udy

Linagliptin Amino group on the piperidine Hydrogen bonding interactions Glu205, Glu206and Tyr662

Eckhardt et al.2007 [202]

C-6 carbonyl of the xanthine Hydrogen bonding interactions Tyr631Quinazoline group Stacking int eract ions Trp629Uracil group Stacking interactions Tyr547

Saxagliptin Amino group (primary) Hydrogen bonding interactions Glu205, Glu206and Tyr662

Metzler et al.2008 [242]

Carbonyl group Hydrogen bonding interact ions Asn710Hydroxyl group on theadamantyl moiety

Hydrogen bonding interactions Tyr 547

Imidate nitrogen Hydrogen bonding interactions Tyr 5474,5-Methanopyrrolidine ring van der Waals interactions Val711, Val656, Tyr662,

Tyr666, Trp659and Tyr547

Nitrile of the cyanopyrrolidine Covalent bond Ser630Sitaglipt in b-Amino group Hydrogen bonding interact ions Glu205, Glu206

and Tyr662Zhu et al. 2013,Kim et al.2005 [163,243]Carbonyl group Hydrogen bonding interact ions Tyr547

Triazolopiperazine Stacking int eract ions Phe357Trifluoromethyl group on

the triazolopiperazine

Ionic Bonds Arg358 and Ser209

Trifluorobenzyl group Hydrophobic interactions Ser630, His740, Trp659,Tyr631, Tyr662and Tyr666

Vildagliptin Amino group Salt bridge interactions Glu205, Glu206 Nabeno et al.2013 [195]Carbonyl group Hydrogen bonding interact ions Asn710

Hydroxyl group on theadamantyl moiety

Hydrogen bonding interactions His126 and Ser209

Imidate nitrogen Hydrogen bonding interactions Tyr547Nitrile of the cyanopyrrolidine Covalent bond Ser630

6 Amino group of t he proline Salt bridge int eract ions Glu205 and Glu206 Yoshida et al.2012 [194]Carbonyl group Hydrogen bonding interact ions Asn710

Quinolyl ring Stacking interactions Phe357CH--p interaction Arg358

Trifluoromethyl on thequinolyl ring

Imperfect interact ion Tyr585

7 (teneligliptin) Amino group of the proline Salt bridge interactions Glu205 and Glu206 Yoshida et al.2012 [197]Carbonyl group Hydrogen bonding interact ions Asn710

Phenyl on the pyrazolyl ring Hydrogen bonding interactions Ser209 and Arg358Hydrogen bonding interactions Val207

Piperazinyl ring CH--p interaction Phe357Pyrazolyl ring Hydrophobic int eract ions Phe357

8 Amino group Salt bridge interactions Glu205 and Glu206 Zhu et al.2013 [163]Trifluoromethyl group on

the triazolopiperazine-Interactions Tyr585 and Arg356

14 Amino group on thequinoline ring

Hydrogen bonding interactions Glu205, Glu206and Tyr662

Maezaki et al.2011 [207]

2-Isobut yl group Hydrophobic int eract ion Phe3572-Oxo group on thepiperazin-2,5-dione

Hydrogen bonding interactions Lys554

5-Oxo group on thepiperazin-2,5-dione

Hydrogen bonding interactions Tyr631

Piperazin-2,5-dione ring Hydrophobic interaction Tyr54715 Amino group at the piperidine

moiety (primary)Salt bridge interactions Glu205 and Glu206 Ikuma et al.

2012 [208]Carbonyl group on thequinoline ring

Hydrogen bonding interactions Tyr631

Carboxyl group on thebenzene ring

Salt bridge interaction Lys554

3H-imidazo[4,5-c]quinolin-4(5H)-one moiety

Stacking interact ions Tyr547

M. Safavi et al.



13/25

of "revious study revealed that the nonlinear *? sha"ed.structure2as moresuitablethan thelinear *I sha"ed. onein)PP6 inhibitory activity( Moreover, theJray crystal structuredetermination of com"ound*6. in com"le 2ith human)PP6 indicated that interaction bet2een the ence, the introducti on of another nonl inear structure, a lin5ed bicyclic heteroaryl !rou" onthe"i"erazineor "i"eridinemoiety, insteadof afusedbicyclicheteroaryl !rou", 2as addressed in thelatter study 2hich ledto discovery of -3*$S,6S.636*-methyl"henyl> "yrazol7yl."i"erazinyl4"yrrolidin$ylcarbonyl4thiazolidine*7., as hi !hly "otent, selecti ve, lon!l asti n! and orally active)PP6 inhibitor( T heJray cocrystal structureof com"ound*7. in )PP6 demonstratedthat thecharacteristicfiveri n!s ofcom"ound *7. fi t i nto theactive site of ) PP6 and the5eyinteraction bet2een the "henyl substi tuent on the "yrazolylri n!and theS$ etensivesubsiteof )PP6 not only raised"otency, but also increased selecti vity *Table 2.( Com"ound*7. si!nifi cantly inhibitedthei ncreaseof "lasma!lucosel evels

after an oral !lucoseloadin K uc5er fatty rats( Com"ound*7.*teneli!li"ti n. has been a""rovedfor thetreatment of T $)Min a"an on une$+$ 30:4(

T he crystal structures of )PP6 in com"le 2ith boundsita!li"tin and alo!li"tin have sho2n that a sub"oc5etformed by the catalytic residue Ser1-+ and nearby residuesis usually occu"ied by ahydro"hobicrin!!rou" such as thetrifluorobenzyl !rou"of sita!li"tin or thebenzonitrileof alo!li"tin( T 2o acidicresidues --9lu$+7 and9lu$+1 --in theS$subsite of )PP6 forms interactions 2ith amine !rou" ofsita!li"tin *Table 2.( T hese interactions bet2een sita!li"ti nand)PP6 !ivealar!eunoccu"ieds"acearoundther i!ht terminal "ortion *the fused heterocyclic rin!. 2hich could be

modified to !enerateane2 seri es of )PP6 inhibitors( Liththis rationale, 2ellestablished clic5 chemistry 2as used to


14/25

derivedfrom)PP6 structures cocrystallised2ith small molecules ori!inatin!fromdifferent chemical classes is no2avitalinvesti !ati on in medicinal chemistry(

ased on the Jray cocrystal structure of some com"ounds, thehydro!en bondin!interaction 2ith ?ys776 maybea""licablei n thenovel desi!n of )PP6 inhibitors( > ence,Maeza5i et al( develo"ed anovel series of noncovalent ence, aseries of C!lucosides 2ith azulenerin!s in thea!lyconemoiety 2as synthesized SAR of azulenederived C!lucosideandtheinhibitory activiti es to2ards hS9? T and hS9?T $ 2eree"lored( Incor"oration of a"henolic hydroyl !rou" at thecentral benzene rin! afforded a more "otent and selecti veS9?T $ inhibitor *18., 2hich eerted astron!and sustainedantihy"er!lycaemic effect in rodent diabetic models(A monocholinesalt of com"ound*18. *M76-. 2as selected

as aclinical candidatefor usein treatin!T $)M 3$;4(A ne2 class of "otent and selectiveS9? T $ inhibitors, by

modifyin!the!lyconesidechain incor"oratin!astructurallynovel dioabicyclo3-($(4octane rin! system, 2as "re"ared 3$$$4( At first, a seri es of C7s"irocyclic C!lycoside2eresynthesized 2ith relati vely !ood "otency and selectivityfor human S9?T $ but subo"ti mal "harmaco5i neti cs 3$$-4(T he medicinal chemistry strate!y by innovative chemistry

M. Safavi et al.



15/25

that allo2ed difficult, yet very desirable, tar!ets to besynthe

sized in an analo!uefriendly fashion and thedevelo"ment ofa "harmaco5ineti csE"harmacodynamics *PBP). modelbrou!ht more ho"e( T hese efforts led to de"rioritisation oftheC7s"irocyclicC!lycosideS9?T $ i nhibitors and focusin!on thedioabicyclo3-($(4octaneclass( I t is believed thatthe brid!ed 5etal system 2ould confer ri!idity 2ith "otentially "ositi veim"act on "otency and selecti vity( Moreover,introducti on of ahydroymethylene> bond donor !rou"at

C7 *in "lace of the s"irocycle. brou!ht more antici"ation

to reducetherateof human PhaseI I metabolism andfurther im"rovement of the "otency( T hese efforts su""orted theadvancement of com"ound *19. *PF+60::$0. into clinicaldevelo"ment that is bein! evaluated for the treatment ofT $)M 3$$$4(

#yas et al( "erformedali!andbased -) 2234 fold

NN

NH

HO

(CH3)3

20 [225]SGLT2 EC50: 3.85 μM

OH

OH

HO

HO

OCH3

O

21 (pseudo-sergliflozin) [227]SGLT2 IC50: 2.45 nMSGLT1/SGLT2 > 200000 fold

O

OH

OH

HO

HO

S

N N

S

22 [228]Inhibition rate of blood glucoselevels in oGTT: 74.85%

O

OH

OH

HO

N

Cl

23 [216]SGLT2 EC50: 161 nMSGLT1/SGLT2: 1.3 fold

Figure 4. Schematic representation of chemical structures of some SGLT2 i nhibit ors tog ether w ith their experimental

inhibitory and selectivity activities.




16/25

structures such as benzisothiazole, indolizineb)!luco"yranoside, thiazolylmethyl"henyl, "yri dazine, thiazole and"yrimidinylmethyl"henyl !lucoside analo!ues( Com"arati vemolecular fi eldanalysis *CoMFA. andcom"arati vemolecular similarity indices analysis *CoMSIA. 2ere used to further e"lore the structural re


17/25

revie2( In this revie2, thestr uctures of somecom"ounds 2ithbiolo!ical "ro"erti es are also "resented( Phenylalanine andcycloheyl alanine derivati ves and imidazo"i"eridinebasedbaminoacidderivati ves 2eredesi!nedbasedon theobservati on that modifi cati on of the"henylalanine, cycloheylalanineor "i"erazinemoiety im"roved the)PP6 "otency by severalfolds( Also the -fluoro"yrrolidine analo!ues obtained byre"lacin!the"yrrolidinerin!com"ounds *1. and*2. sho2edmore acti vity com"ared to "arent com"ound 3;0,0+4( Sincebicyclo3-(-(+4octane derivative2ith "yrrolidine$carbonitrile2as "reviously re"orted to bea"otent )PP6 inhibitor 304,azobicyclo3-(-(+4octanecom"ounds 2eresynthesized( T hediscovery of ana!li"ti n 2as accordin!to studies sho2edthat "yrazolo3,7a4"yrimidine functions as a bioisostere conveyin!much metabolicstability andsafety 30-4(

A costly com"onent of dru! discovery a""roaches isstructurebasedscreenin!*doc5i n!., 2hich is adesi!n strate!yfor ne2chemical enti ti es, or o"ti misati on of leadcom"oundsidentified by other methods, usin! the -) structure of the)PP6( T he -) structure of )PP6 could be obtained by

Jray or nuclear ma!neticresonancestudies or fromhomolo!y models( T he "rotein data ban5 is a re"ository for the-) structural data of "roteins( T he crystal structures of)PP6 havebeen "reviously disclosed and the discovery ofteneli!li"tin "erformedby aidof mentionedin sil icomethods2hich com"rise com"utati onally assessed li!andbindin!interactions 2ith )PP6( on"e"tidomimetic inhibitors of)PP6 such as -amino"i"eridines 2ith bicycliclactams substituents 2ereori!inated from sita!li"tin --a"e"tidomimetic)PP6 inhibitor, Jray crystallo!ra"hic structure alon! 2ithmolecular modellin! 3$+4( Also noncovalent


18/25

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selenium su""lementation in "ati ents

2ith ty"e$ diabetes/ effects on !lucose

homeostasis, oidativestr ess, andli"id

"rofil e( Am T her

$+-Published online$0 A"r $+-

doi/+(+0:EMT (+b+-e-;$10:7f

17( avaeii!@eh M, Rahimifard M,

Pour5halili , et al( Multi or!an

"rotectiveeffects of cerium oide

nano"arti cleEselenium in diabeticrats/

evidencefor moreefficiency of

nanocerium in com"arison to metal form

of cerium( Asian Anim #et Adv

$+$:/1+7$

11( T abatabaeiMalazy ', ?ari @ani ,

Abdollahi M( A novel mana!ement of

diabetes by means of stron!anti oidants=

combination( Med > y"otheses I deas

$+-:/$7-+

1:( Pour5hali li , >osseini A,

iliAhmadabadi A, et al( iochemical

and cellular evidenceof thebenefi t of a

combinati on of cerium oide

nano"arti cles and selenium to diabetic

rats( Lorld )i abetes $+$/$+6+

1;( )r e2s 9, Bri ""eit)r e2s P, )ufer M(

'idativestress and betacell

dysfuncti on( Pfl u!ers Arch

$++61+/:+-;




20/25

10( Abdollahi M, F ooladian F, %mami ,

et al( Protection by si ldenafi l and

theo"hyllineof lead acetateinduced

oidati vestress in r at submandibular

!landandsaliva( > um%" T oicol

$++-$$/7;:0$

:+( AstaneieF, Afshari M, Mo@tahedi A,

et al( T otal anti oidant ca"acity and

levels of e"idermal !ro2th factor and

nitri coidein blood andsali vaof

insulinde"endent diabeti c"ati ents(

Arch Med Res $++7-1/-:1;

:( Farshchi A, i 5far S, Seyedifar M,

Abdollahi M( %ffect of chromium on

!lucoseand li"id "rofiles in "atients 2ith

ty"e$ diabetes ametaanalysis revie2 of

randomized trials( Pharm Pharm Sci

$+-1/006

:$( >osseini A, Abdollahi M( I t is timeto

formulate an antioidant miture for

mana!ement of diabetes and its

com"licati ons/ noticefor "harmaceuti cal

industri es( Int Pharm $+$;/1+

:-( Bamyab S, > e@r ati S, Bhanavi M,

Mohammadirad A( > e"ati cmechanisms

of theLalnut antidiabeti ceffect in mice(

Cent %ur iol $++7/-+60

:6( ?ari @ani , Afshari M,

AstanehiAs!hari F, et al( %ffect of

shortterm carvedil ol thera"y on salivary

and "lasmaoidati vestress "arameters

and "lasma!lucoselevel in ty"eI I

diabetes( T hera"y $++1-/0$-

:7( Milani %, i5far S, Bhorasani R, et al(

Reducti on of diabetesinduced oidati ve

str ess by "hos"hodiesteraseinhibitors inrats( Com"iochem Physiol C

T oicol Pharmacol $++76+/$77

:1( Mohseni Salehi Monfared SS, ?ari @ani ,

Abdollahi M( I slet trans"lantation and

antioidant mana!ement/

acom"rehensiverevie2(

Lorld 9astroenterol $++07/7-1

::( Radfar M, ?ari @ani , > ad@i babaieM,

et al( %ffects of "entoifyllineon

oidativestr ess and levels of %9F and

' in blood of diabeticty"e$ "atients

arandomized, doublebli nd "lacebo

controlled clinical trial(

iomed Pharmacother $++770/-+$1:;( Sar5hail P, Rahmani"our S,

Fadyevatan S, et al( Anti diabeticeffect of

Phlomis anisodonta/ effects on he"ati c

cells li"id "eroidation and antioidant

enzymes i n e"erimental diabetes(

Pharmacol Res $++:71/$11

:0( #osou!h9hanbari S, Rahimi R ,

Bharabaf S, et al( %ffects of Sature@a

5huzestanicaon serum !lucose, li"ids and

mar5ers of oidativestress in "atients

2ith ty"e$ diabetes mellitus/

adoubleblind randomized controlled

trial( %vid ased Com"lement

Alternat Med $++:/617:+

;+( olzano B( i !uanides/ reasons for

2ithdra2al of dru!s and remainin!

indicati ons( ActaMedAustriaca

0:;7/;7;

;( ?uft ), Schmullin!RM, %!!stein M(

?acti cacidosis i n bi!uanidetreated

diabeti cs/ arevie2 of --+ cases(

)i abetolo!ia0:;6/:7;:

;$( Ansari 9, Mo@tahedzadeh M, B a@baf F,

et al( >o2does blood !lucosecontrol

2ith metformin influenceintensive

insuli n "rotocolsO%videncefor

involvement of oidativestress and

inflammatory cyto5ines( Adv T her

$++;$7/1;:+$

;-( )efronzo RA, 9oodman AM( %ffi cacy of

metformin in "atients 2ith

noninsulinde"endent diabetes mellitus(

T heMulticenter Metformin Study

9rou"( %n!l Med 007---/760

;6( > olman RR, Paul SB , ethel MA, et al(

+year foll o2u" of intensive!lucose

control in ty"e$ diabetes( %n!l Med

$++;-70/7::;0

;7( Morsin5 ?M, Smits MM, )iamant M(

Advances in "harmacolo!icthera"ies for

ty"e$ diabetes( Curr Atheroscler Re"

$+-7/-+$. Overview of recent advances in

pharmacological therapy for T2DM,

focusing on agents that recentl y have

been approved and those for which

approval is pending.

;1( ail ey C, T urner R C( Metformin(

%n!l Med 001--6/7:60

;:( Cusi B , Consoli A, )efronzo RA(

Metaboli ceffects of metformin on

!lucoseand lactate metaboli sm in


Clin %ndocri nol Metab

001;/6+701:

;;( > undal RS, Brssa5 M, )ufour S, et al(Mechanism by 2hich metformin reduces

!lucose"roducti on in ty"e$ diabetes(

)iabetes $+++60/$+1-0

;0( )el Prato S, Marchetto S, Pi"itoneA,

et al( Metformin and freefatty acid

metabolism( )iabetes Metab Rev

007/--6

0+( Stumvoll M, ur@han , Perr iell o 9,

et al( Metaboli ceffects of metformin i n


%n!l Med 007---/77+6

0( Merri ll 9F, Burth %, >ardie )9,

Linder LL( AICA ri bosideincreases

AMPacti vated"rotein 5inase, fatty acid

oidati on, and !lucoseu"ta5e in rat

muscle( Am Physiol 00:$:-/+:$

0$( K hou 9, Myers R, ? i , et al( Roleof

AMPactivated "rotein 5inasein

mechanism of metformin acti on(

Clin Invest $+++;/1::6

0-( Palumbo P( Metformin/ effects on

cardiovascular ris5 factors in "ati ents

2ith noninsulinde"endent diabetes

mellitus( )iabetes Com"licati ons

00;$/+0

06( 9arber A, )uncan T 9, 9oodman AM,

et al( %ffi cacy of metformin i n ty"eI I

diabetes/ results of adoublebli nd,

"lacebocontr oll ed, doser es"onsetr ial(Am Med 00:+-/60:

07( Sheehan MT ( Curr ent thera"eutic

o"tions in ty"e$ diabetes mellitus/

a"racti cal a""roach( Clin Med Res

$++-/;0$++. An informative review on the

management of T2DM from the

ini tiation of oral agents through dual

(potentially triple) therapy onto

insulin initiation.

01( Stan!M, Lyso2s5i )B , utlerones )(

I ncidenceof lacticacidosis in metformin

users( )iabetes Care000$$/0$7:

0:( Stolar ML, > oo!2erf , 9orsho2 SM,et al( Mana!in! ty"e$ diabetes/ !oin!

beyond!lycemiccontrol( Mana!

CarePharm $++;6/s$0

0;( Rendell MS, Bi rchain LR(

Pharmacothera"y of ty"e$ diabetes

mellitus( Ann Pharmacother

$+++-6/;:;07

00( haratam P#, Patel )S, I


21/25

+$( ryan , CraneA, #ilaCarril es L> ,

et al( Insulin secreta!o!ues, sulfonylurea

rece"tors and B*AT P. channels(

Curr Pharm )es $++7/$100:1

+-( 9ri bbleF M, Reimann F( )i fferential

selecti vity of i nsulin secreta!o!ues/

mechanisms, clinical im"licati ons, and

dru!interacti ons(

)iabetes Com"lications $++-:/7

+6( Perfetti R, Ahmad A( ovel sulfonylurea

and nonsulfonylureadru!s to "romote

thesecretion of insuli n(

T rends %ndocrinol Metab

$+++/$;$-

+7( a5 F, Pedersen '( 9li clazideand

insulin action in human muscle(

)iabetes Res Clin Pract 006*$./16

+1( Pedersen ', > otherielsen ', a5 ,

et al( %ffects of sulfonylureas on

adi"ocyte and s5eletal muscleinsulin

acti on in "ati ents 2ith

noninsul inde"endent diabetes mellitus(Am Med 000+*1A./$$;

+:( Boryt5o2s5i MT ( Sulfonylureatreatment

of ty"e$ diabetes mellitus/ focus on

!lime"iride( Pharmacothera"y

$++6$6/1+1$+

+;( asi5 M( 9lime"iri dein daily "ractice(

Prze!l ?e5 $++-1+/6+0$

+0( asit A, Riaz M, F a22ad A(

9lime"ir ide/ evidencebased facts, tr ends,

and observations *9IFT S.( #asc> ealth

Ri s5 Mana! $+$;/61-:$

+( i @l straP, ? utterman A, Russel F9,

et al( Interaction of sul"honylurea

derivatives 2ith vascular AT Psensitive

"otassi um channels i n humans(

)iabetolo!ia001-0/+;-0+

( ?eeT M, Chou T F( Im"air ment of

myocardial "rotecti on in ty"e$ diabeti c

"atients( Cli n % ndocrinol Metab

$++-;;/7-:

$( Cam"bell RB ( 9li me"iri de/ roleof a

ne2 sulfonylureain thetreatment of


Ann Pharmacother 00;-$/+667$

-( )ornhorst A( Insuli notro"icme!li tinide

analo!ues( ?ancet $++-7;/:+01

6( MalaisseL( Pharmacolo!y of theme!liti nideanalo!s/ ne2tr eatment

o"ti ons for ty"e$ diabetes mellitus(

T reat %ndocrinol $++-$/6+6

7( ?i , T ian > , ? i G, et al( Im"rovement

of i nsulin sensitivity and betacell

function by nate!linideand re"a!linide

in ty"e$ diabetic"atients a

randomized controlled doublebli nd and

doubledummy multicentreclinical trial(

)iabetes 'bes Metab $++:0/77;17

1( Rosenstoc5 , > assman )R,

Madder R) , et al( Re"a!linideversus

nate!linidemonothera"y/ arandomized,

multi center study( )iabetes Care

$++6$:/$17:+

:( >u S, Lan!S, Fanell i , et al(

Pancreati cbetacell B*AT P. channel

acti vity and membranebindin! studies

2ith nate!linide/ acom"arison 2ith

sulfonylureas and re"a!linide(

Pharmacol %" T her $+++$0-/6667$

;( Mc?eodF( Cli nical "harmaco5inetics of

nate!linide/ ara"idlyabsorbed,

shortactin!insuli notro"ica!ent(

Cli n Pharmaco5inet $++66-/0:$+

0( Chachin M, amadaM, Fu@itaA, et al(

ate!linide, a)"henylalaninederivative

lac5in!either asulfonylureaor

benzamido moiety, s"ecifi cally inhibits"ancreati cbetacellty"eB*AT P. channels(

Pharmacol % " T her

$++--+6/+$7-$

$+( Cam"bell I L( ate!linidecurrent and

future rolein the treatment of "atients

2ith ty"e$ diabetes mellitus( I nt

Clin Pract $++770/$;$;

$( S"encer CM, Mar5ham A( T ro!litazone(

)r u!s 00:76/;0+

$$( aeMA, Rhee> , Son!( T ro!li tazone

but not rosi!li tazoneinduces 9 cell

cyclearrest and a"o"tosis in human and

rat he"atomacell lines( T oicol ? ett

$++--0/1::7

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Im"rovement in !lucosetoleranceand

insulin r esistancein obesesub@ects treated

2ith tr o!li tazone( %n!l Med

006--/;;0-

$6( Suter S? , olan , Lall aceP, et al(

Metaboliceffects of ne2 oral

hy"o!lycemic a!ent CS+67 in I))M

sub@ects( )iabetes Care00$7/0-$+-

$7( 5iarvinen >( T hiazolidinediones(

%n!l Med $++6-7/+1;

$1( '5unoA, T amemoto > , T obeB , et al(

T ro!litazoneincreases thenumber of

small adi"ocytes 2ithout the chan!eof

2hiteadi"osetissuemass in obese

K uc5er rats( Clin I nvest

00;+/-761

$:( Picard F, Au2er ( PPAR *!amma. and

!lucosehomeostasis( Annu Rev utr

$++$$$/1:0:

$;( )efronzo RA( antin!?ecture( F romthe

triumvirate to theominous octet/ ane2

"aradi!m for the treatment of

ty"e$ diabetes mellitus( )iabetes

$++07;/::-07

$0( Maeda, T a5ahashi M, Funahashi T ,

et al( PPAR!ammali!ands i ncrease

e"ressi on and "lasmaconcentrati ons of

adi"onecti n, an adi"osederived "rotein(

)iabetes $++7+/$+060

-+( MatsudaM, Shimomura I , SataM, et al(

Role of adi"onectin i n "reventin!

vascular stenosis( T hemissi n!lin5 of

adi"ovascular ais( i ol Chem

$++$$::/-:6;:0

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et al( 'nce and t2icedaily dosin!2ith

rosi!li tazoneim"roves !lycemiccontrol

in "ati ents 2ith ty"e$ diabetes(

)iabetes Care$++$6/-+;7

-$( Par5 BS, Ciaraldi T P, AbramsCarter ?,

et al( T ro!litazoner e!ulation of !lucosemetaboli sm in human s5eletal muscle

cultures fromobesety"eI I diabetic

sub@ects( Cli n %ndocrinol Metab

00;;-/1-16-

--( I dris I , 9ray S, )onnell y R(

Rosi!litazoneand "ulmonary oedema/

an acutedosede"endent effect on human

endotheli al cell "ermeabil ity(

)iabetolo!ia$++-61/$;;0+

-6( Pa!eR? , 9ozans5y LS, Ruscin M(

Possibleheart failure eacerbation

associated 2ith rosi!li tazone/ casere"ort

and literaturerevie2( Pharmacothera"y

$++-$-/06776-7( Pa"oushe5 C( T heQ!litazones/

rosi!li tazoneand "io!litazone( 'bstet

9ynaecol Can $++-$7/;7-:

-1( 9im > , Cheon , Ryu > , eon R(

)esi!n and synthesis of benzoazole

containin! indoleanalo!s as "eroisome

"roliferatoracti vatedrece"tor!ammaE

deltadual a!onists( i oor!Med

Chem ?ett $+$/-+7:1

-:( Matsumoto B, ano M, Miya5eS, et al(

%ffects of vo!liboseon !lycemic

ecursi ons, i nsulin secretion, and insuli n

sensitivity in noninsuli ntreated

I ))M "atients( )iabetes Care00;$/$711+

-;( Shinoza5i B, Suzu5i M, I 5ebuchi M,

et al( I m"rovement of insulin sensitivity

and dysli "idemia2ith ane2

al"ha!lucosidaseinhibitor, vo!libose, in

nondiabeti chy"erinsulinemic sub@ects(

Metabolism 00167/:-:




22/25

-0( Scheen A( Is there arole for

al"ha!lucosidaseinhibitors in the

"revention of ty"e$ diabetes mellitusO

)r u!s $++-1-/0--7

6+( ohnston PS, ? ebovitz > %, Coniff R F,

et al( Advanta!es of al"ha!lucosidase

inhibiti on as monothera"y i n elderly

ty"e$ diabetic"atients( Cli n

%ndocri nol Metab 00;;-/77$$

6( alfour A, McT avish )( Acarbose(

An u"date of its "harmacolo!y and

thera"euticusein diabetes mellitus(

)r u!s 00-61/+$776

6$( Santeusanio F, Com"a!nucci P(

A ris5benefit a""raisal of acarbosei n the

mana!ement of noninsulinde"endent

diabetes mellitus( )ru! Saf

006/6-$66

6-( Reuser A, Lisselaar >A( An evaluation

of the "otential sideeffects of

al"ha!lucosidase inhibitors used for the

mana!ement of diabetes mellitus( %ur Clin I nvest 006$6*-./0$6

66( 9en!P, Giu F, K hu , ai 9( Four

acarviosincontainin! oli!osaccharides

identifi ed fromStre"tomyces

coelicoflavus K 9+171 are"otent

inhibitors of al"haamylase(

Carbohydr Res $++;-6-/;;$0$

67( van 9enu!ten R%, van Raalte )> ,

)iamant M( )oes !luca!onl i5e "e"tide

rece"tor a!onist thera"y addvaluein

the tr eatment of ty"e$ diabetesOFocus

on eenati de( )iabetes Res Clin Pract

$++0;1*Su""l ./S$1-6

61( Par5s M, Rosebrau!h C( Lei!hin! ri s5sand benefits of lira!lutidetheF )A=s

revie2of ane2 antidiabeticthera"y(

%n!l Med $++-1$/::6:

6:( i 5far S, Abdollahi M, Salari P( T he

efficacy and tolerability of eenati dein

com"arison to "lacebo asystemati c

revie2 and metaanalysis of randomized

clinical tri als( Pharm Pharm Sci

$+$7/-+

6;( auc5 MA, aranov ', Ri tzel RA,

Meier ( )o curr ent incretin mimetics

e"loit the full thera"eutic"otential

inherent in 9?P rece"tor stimulationO

)iabetolo!ia$+-"ublished onli ne0 un $+-

doi/+(++:Es++$7+-$07-1

60( )r uc5er ), auc5 MA( T hei ncretin

system/ !luca!onli5e "e"tide rece"tor

a!onists and di"e"tidyl

"e"ti dase6 inhibitors in ty"e$ diabetes(

?ancet $++1-1;/101:+7

7+( > olst ( T he"hysiolo!y of !luca!onli5e

"e"tide( Physiol Rev $++:;:/6+0-0

7( Pos"isil i5 A, Stafford S9, )emuth >U,

et al( ?on!term treatment 2ith the

di"e"tidyl "e"tidaseI # inhibitor P-$E

0; causes sustained im"rovements in

!lucosetolerance, insuli n sensitivity,

hy"erinsulinemia, and betacell !lucose

res"onsiveness in #)F *faEfa. K uc5er

rats( )i abetes $++$7/06-7+

7$( Cho M, Merchant C%, Bieffer T (

T ar!eti n! the !luca!on rece"tor family

for diabetes andobesity thera"y(

Pharmacol T her $+$-7*-./$6::;

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Structureof thehuman !luca!on class

9"roteincou"ledrece"tor( ature

$+-600*:670./6660

76( 9arber A( ?on!actin!!luca!onli5e

"e"tide rece"tor a!onists/ arevie2 of

their efficacy and tolerability(

)i abetes Care $+-6*Su""l $./S$:0;677( ond A( %enatide*yetta. as anovel

treatment o"ti on for ty"e$ diabetes

mellitus( Proc*ayl Univ Med Cent.

$++10/$;6

71( Par5es )9, Pittner R, od5aC, et al(

I nsulinotro"ic actions of eendin6 and

!luca!onl i5e"e"tide in vivo and in

vitro( Metabolism $++7+/7;-0

7:( @ err eB?, Madsen ?L, Andersen S,

et al( 9luca!onl i5e Pe"tide rece"tor

a!onists acti vate rodent thyroid Ccells

causin! calcitonin release and Ccell

"roli feration( %ndocrinolo!y

$++7/6:-;1

7;( Fr an5s AS, ? eeP>, 9eor!eCM(

Pancreati ti s/ a"otential com"li cati on of

lira!luti deOAnn Pharmacother

$+$61/76:7-

70( La@cber! %, Amarah A( ?ira!lutidein

the mana!ement of ty"e$ diabetes(

)r u!) es )evel T her $++6/$:00+

1+( Au!eri ), Robl A, etebenner )A,

et al( )i scovery and "reclinical "rofi leof

Saa!li"tin *MS6::;./ ahi!hly

"otent, l on!acti n!, orally acti ve

di"e"tidyl "e"tidaseI # i nhibitor for the

treatment of ty"e$ diabetes(

Med Chem $++76;/7+$7-:

1( 9all2itz ( Small molecule

di"e"tidyl"e"tidaseI # i nhibitors under

investi !ati on for diabetes mellitus

thera"y( % "ert '"in Investi! )ru!s

$+$+/:$--$

1$( Saisho , I toh >( )i"e"tidyl

"e"tidase6 inhibitors and an!ioedema/

aclass effectO )iabet Med

$+--+/607+

1-( K hu ? , ? i , Giu ?, et al( )esi!n and

synthesis of 6*$,6,7T ri fluoro"henyl.

butane,-diamines as ) i"e"tidyl

Pe"ti daseI# I nhibitors( ChemMedChem

$+-;/+61

16( Bi m L, %!an M( T herole of incretinsin !lucosehomeostasis and diabetes

tr eatment( Pharmacol Rev

$++;1+/6:+7$

17( > olst , #i lsboll T , )eacon CF( T he

incretin system andits role in


Mol Cell % ndocri nol $++0$0:/$:-1

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res"onsiblefor their de!radation in

human serum( %ur i ochem00-$6/;$0-7

1:( Someya, T ahara A, a5ano R, et al(

Pharmacolo!ical "rofileof ASP;60:, a

novel, selecti ve, and com"eti ti ve

di"e"tidyl "e"tidaseI # inhibitor, i n vitro

and in vivo( aunyn Schmiedeber!s

Arch Pharmacol $++;-::/$+0:

1;( 9u"taR , Lalun@ SS, T o5ala RB , et al(

%mer!in! dru! candidates of di"e"tidyl

"e"tidaseI # *)PP I #. inhibitor class for

thetr eatment of T y"e$ )iabetes(

Curr )r u!T ar!ets $++0+/:;:

10( Scheen A( 9li"tins *di"e"tidyl

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"otential im"ortanceof selecti vity over

di"e"tidyl "e"tidases ; and 0( )iabetes

$++776/$0;;06

:( abu A( Cana!liflozin for thetreatment

of ty"e$ diabetes( )ru!s T oday *arc.

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Cli n Pharmacol $+$7$/67:1-

:-( 9eri ch %( Roleof the5idney in normal

!lucosehomeostasis and in the

hy"er!lycaemiaof diabetes mellitus/

thera"euticim"licati ons( )iabet Med

$++$:/-16$

M. Safavi et al.



23/25

:6( Lri!ht %M, > irayamaA, ?oo)F(

Activesu!ar trans"ort in health and

disease( I ntern Med $++:$1/-$6-

:7( Rahmoune> , T hom"son PL,

Lard M, et al( 9lucosetrans"orters i n

human renal "roimal tubular cells

isolated from theuri neof "atients 2ith

noninsul inde"endent diabetes( )iabetes

$++776/-6$:-6

:1( eumill er , LhiteR r,

Cam"bell RB( Sodium!lucose

cotrans"ort inhibitors/ "ro!ress and

thera"euti c"otential in ty"e$ diabetes

mell itus( )ru!s $++:+/-::;7

::( %l 5inson S, Scott ? ( Cana!li flozin/ first

!lobal a""roval( )ru!s $+-:-/0:0;;

:;( > ardman T C, )ubrey SL(

)evelo"ment and "otenti al role of

ty"e$ sodium!lucosetrans"orter

inhibitors for mana!ement of

ty"e$ diabetes( )iabetes T her

$+$/--67:0( omuraS, Sa5ama5i S, > on!u M, et al(

)iscovery of cana!liflozin, anovel

C!lucoside2ith thio"henerin!, as

sodiumde"endent !lucosecotrans"orter

$ i nhibitor for thetreatment of

ty"e$ diabetes mellitus( Med Chem

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;6( 9reen ), F latt PR, ail ey C(

)i "e"tidyl "e"tidaseI# *)PP I #.

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for the treatment of ty"e$ diabetes(

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for thetreatment of diabetes/ "art I I /

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;:( %dmondson S), Mastracchio A,

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betasubstituted "henylalaninederived

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6amino"henylalanineand6aminocycloheylalaninederivati ves as

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treatment of diabetes( ioor! Med

Chem ?ett $++::/7;7-:

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bicyclo3-(-(+4 octanederivati ves as

di"e"tidyl "e"tidase6 inhibitors for thetreatment of ty"e$ diabetes( ioor!Med

Chem ?ett $++$+/-7$7

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cyano"yrr oli dinyl4$ooethylamino.

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et al( Fused bicyclic

heteroaryl"i"erazinesubstituted

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of vildagliptin with DPP-4 and the

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Synthesis of novel "otent di"e"tidyl

"e"tidaseI # inhibitors 2ith enhanced

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terminal amino acid al5yl si dechain

and thecyclo"ro"yl !rou" of al"ha

aminoacyllcis6,7methano"rolinenitrile

based inhibitors( Med Chem

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teneli!li"tin *-3*$S,6S.636*-methyl

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ahi!hly "otent, selecti ve, lon!lasti n!

and orally acti vedi"e"ti dyl "e"tidaseI #

inhibitor for thetreatment of

ty"e$ diabetes( ioor! MedChem

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thiazolidine com"ounds as anovel series

of "otent and stable)PPI# inhibitors(

i oor! Med Chem $++16/-11$:

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et al( ?ead o"timizati on of 3*S.!amma

*arylamino."rolyl4thi

the importance of synthetic drugs for type 2 diabetes drug discovery - expert opin. drug discov....

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