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Applications of Deuterium-Labelled Compounds in Total Synthesis and
Drug Development
Kai Yu Zakarian Group
University of California, Santa Barbara 10/18/2018
From First Approved Deuterated Drug Back to Deuterium
• First deuterated drug from Teva Pharmaceuticals • Approved by FDA in 2017• The treatment of chorea associated with Huntington’s disease• Beneficial deuterium effect: reduce rate of active metabolite demethylation
driven by CYP2D6• Higher efficacy at a lower doses and with a longer duration of action
• One of two stable isotopes of hydrogen• Natural abundance: 0.0115% (earth)• First discovered specterscopically and named by Harold Urey in 1931• Deuterium won Urey the Nobel Prize in Chemistry in 1934.• Famous by heavy water and “hydrogen bomb”
NH
OH
O
O
D3CD3C
deutetrabenazine(Austedo)
H21Deuterium
2.0141u
Application of Deuterated Compounds
Drug development: enhance metabolic stability
Total synthesis: modify reaction selectivity
Clarification of organic reaction mechanisms
Elucidation of biosynthetic routes
Mass spectrometry internal standards
Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid M. Angew. Chem. Int. Ed. 2018, 57, 1758-1784.
Application of Deuterated Compounds
Drug development: enhance metabolic stability
Clarification of organic reaction mechanisms
Elucidation of biosynthetic routes
Total synthesis: modify reaction selectivity
Mass spectrometry internal standards
Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid M. Angew. Chem. Int. Ed. 2018, 57, 1758-1784.
The Kinetic Isotope Effect
En = n + 1 hν
ν = 12*+k-
µ = /1 • /2/1 +/2µC-H = 0.92
µC-D = 1.71
• Kinetic isotope effect (KIE) is observed in between the isoptopically labelled molecules showing different
reaction rates.• Primary KIE is attributed to a bond breaking event at the C-H/C-D bond.• Vibrational frequency is relative to reduced mass µ.• For C-D, lower vibrational frequency and lower zero-point energy (ZPE)
Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid M. Angew. Chem. Int. Ed. 2018, 57, 1758-1784.
The Kinetic Isotope Effect
Anslyn, E. V.; Doughery, D. A. Modrn Physical Organic Chemistry; University Science Books, 2006
• Secondary KIE is the effect attributed to a rehybridization or arises from isotopic substitution remote
from the bonds undergoing reaction.• The large difference in force constant for the out-of-plane bend of an sp3 hybrid versus and sp2 hybrid
means that there will be a significant difference in ZPE differences between C-H and C-D bonds.• Similarly, a large difference in the frequency of the in-plane bend exists between sp2 and sp hybrids
pote
ntia
l ene
rgy
reaction cooridnate
larger activation energy for the C-D bond
potential energy well for the out-of-plane bend at an sp3 center
potential energy well of a mix of sp2 and sp3 character at the T.S.
potential energy well for the out-of-plane bend at an sp2 center
• kH/kD > 1• usually at 1.1~1.2• normal KIE
The Kinetic Isotope Effect
Anslyn, E. V.; Doughery, D. A. Modrn Physical Organic Chemistry; University Science Books, 2006
• Secondary KIE is the effect which is attributed to a rehybridization or arises from isotopic substitution
remote from the bonds undergoing reaction.• The large difference in force constant for the out-of-plane bend of an sp3 hybrid versus and sp2 hybrid
means that there will be a significant difference in ZPE differences between C-H and C-D bonds.• Similarly, a large difference in the frequency of the in-plane bend exists between sp2 and sp hybrids
pote
ntia
l ene
rgy
reaction cooridnate
larger activation energy for the C-H bond
potential energy well for the out-of-plane bend at an sp2 center
potential energy well of a mix of sp2 and sp3 character at the T.S.
potential energy well for the out-of-plane bend at an sp3 center
• kH/kD < 1• usually at 0.8~0.9• inverse KIE
The Kinetic Isotope Effect
• Secondary KIE is the effect which is attributed to a rehybridization or arises from isotopic substitution
remote from the bonds undergoing reaction.• The large difference in force constant for the out-of-plane bend of an sp3 hybrid versus and sp2 hybrid
means that there will be a significant difference in ZPE differences between C-H and C-D bonds.• Similarly, a large difference in the frequency of the in-plane bend exists between sp2 and sp hybrids
Kurtz, K. A.; Fitzpatrick, P. F. J. Am. Chem. Soc. 1997, 119, 1155.Anslyn, E. V.; Doughery, D. A. Modrn Physical Organic Chemistry; University Science Books, 2006
N
NR
NH
N
O
OFAD
R CO2-
NH3+R CO2-
NH3+
HBase
Path A
Path B
N
NR
NH
N
O
O
R CO2-
NH3+
N
NR
NH
N
O
O
R+H3N CO2-
NH
NR
NH
HN
O
O
+H2N
R
CO2-
FADH
+
• Path A: nucleophilic addition to the flavin
• Path B: single electron transfer to the flavin followed by the coupling between two radicals.
The Kinetic Isotope Effect
• Secondary KIE is the effect which is attributed to a rehybridization or arises from isotopic substitution
remote from the bonds undergoing reaction.• The large difference in force constant for the out-of-plane bend of an sp3 hybrid versus and sp2 hybrid
means that there will be a significant difference in ZPE differences between C-H and C-D bonds.• Similarly, a large difference in the frequency of the in-plane bend exists between sp2 and sp hybrids
Kurtz, K. A.; Fitzpatrick, P. F. J. Am. Chem. Soc. 1997, 119, 1155.Anslyn, E. V.; Doughery, D. A. Modrn Physical Organic Chemistry; University Science Books, 2006
• Path A rds: sp2 to sp3
• Path B rds: sp2 retained• observed KIE = 0.84• secondary inverse KIE• strongly supported the nucleophilic mechanism
N
NR
NH
N
O
O
X NO
O
X = H or D
Path A
Path BN
NR
NH
N
O
O
X NO
O
N
NR
NH
N
O
O
NO
OX
FAD
slow fast
Applying Deuterium KIE in Total Synthesis
Total synthesis: modify reaction selectivity
HN
OHO
O
O
O OMe
O
HO
OH
fredericamycin A
N
OR
NR’
aziridinomitosenes
N
OO
O O
O
Me
Me
H
H
Me HMe
Me
norzoanthmine
N
Me
O
Me
OMe
Me
Me
O
O
NMe
OO
MeCl
MeMeR1
H
R2
N-methylwelwitndolinone C
Me OSO3-
Cl
Cl
OSO3-
Cl Cl
Cl Cl
danicalipin A
Fredericamycin A
HN
OHO
O
O
O OMe
O
HO
OH
fredericamycin A
• Antitumor antibiotic agent isolated from Steptomyces griseus• Vitro cytotoxic acitivity and efficacious antitumor acitvity• Procaryotic RNA/protein synthesis are inhibited • Synthesized by Derrick L. J. Clive et al. in 1994.• Key step — 5-exo-digonal radical spirocyclization• Possibly the first application of deuterium KIE in total synthesis
O
O
OH
OH
O
O
OMe
quinone system offredericamycin A
Clive, D. L. J. Tetrahedron 1993, 49, 7917-7930.Clive, D. L. J. J. Am. Chem. Soc. 1994, 116, 11275-11286.
OMe
OMeTMSO
Ph
PhSeCl
91% yield
OMe
OMe
Ph
PhSeO
Ph3SnHAIBN
benzene, reflux
OMe
OMe
Ph
O
Ph
O
OMe
OMe
Ph3SnHPh
O
OMe
OMe
H
95% yield
Model study
Fredericamycin A
Clive, D. L. J. Tetrahedron 1993, 49, 7917-7930.Clive, D. L. J. J. Am. Chem. Soc. 1994, 116, 11275-11286.
HN
OHO
O
O
O OMe
O
HO
OH
fredericamycin A
O
O
OH
OH
O
O
OMe
quinone system offredericamycin A
OMe
OMe
Ph
PhSeO OMe
OMeOMe
Ph3SnH, AIBNbenzene, reflux
OMe
OMe
Ph
O
Ph
O
O
OMe
OMeOMe
OMe
OMeOMe
OMe
HPh
O
O
OMe
OMeOMe
OMe
H
Ph3SnH Ph3SnH
O
O
OMe
OMeOMe
OMe
HPh
HPh
O
OMe
OMe
HOMe
OMe
OMe
48% yield40% yield
Unexpected intramolecular hydrogen abstraction
Fredericamycin A: Deuterium KIE suppress the hydrogen migration
Clive, D. L. J. Tetrahedron 1993, 49, 7917-7930.Clive, D. L. J. J. Am. Chem. Soc. 1994, 116, 11275-11286.
Br
OH
OMe
Ph
OMe
OMeOMe
CD3OTsNaH, DMF
81% yieldBr
O
OMe
Ph
OMe
OMeOMe
D3C
Enhancing the stability of peri-methoxy group
nBuLi,cyclopentane-carboxaldehyde
O
OMe
Ph
OMe
OMeOMe
D3C
OH
88% yield
1. DDQ2. TMSOTf3. PhSeCl
O
OMe
Ph
PhSeO OMe
OMeOMe
D3C
48% yield
O
OMe
Ph
PhSeO OMe
OMeOMe
D3C Ph3SnH, AIBNbenzene, reflux Ph
O
O
OMe
OMeOMe
OMe
DDD Ph
O
OCD3
OMe
HOMe
OMe
OMe
O
O
OMe
OMeOMe
OMe
DPh
H
DD
+
75% yield 4% yield
Fredericamycin A: Deuterium KIE suppress the hydrogen migration
Clive, D. L. J. Tetrahedron 1993, 49, 7917-7930.Clive, D. L. J. J. Am. Chem. Soc. 1994, 116, 11275-11286.
Ph
O
OR
OMe
HOMe
OMe
OMeO
O
OR
OMe
OMe
OMe
OMe1.O32. P(OMe)3
94% yield
CAN
R=CH3, 84%R=CD3, 78%
O
O
OR
OMe
O
O
OMe BBr3
R=CH3, 89%R=CD3, 68%
O
O
OH
OH
O
O
OMe
Later revomal of deuterated unit
OCX3
OMe
Ph
PhSeO OMe
OMeOMe
Ph
O
OCX3
OMe
HOMe
OMe
OMe
O
O
OMe
OMeOMe
OMe
XPh
H
XX
+
Ph3SnH, AIBNbenzene, reflux
X = HX = D
48% yield75% yield
40% yield4% yield
kH/kD = 15.6
Kenetic Isotopic effect
Aziridinomitosenes
Vedejs, E. J. Am. Chem. Soc. 2002, 124, 748-749.
• Metabolic activation of FR66979 and FR900482 generates
intermediate A having an ability to cross-link DNA.• Leucoaziridinomitosenes B are responsible for the antitumor
activity of the mitomycin antibiotics.• Delocalization helps to stabilize carbonyl derivatives C, which
had been synthesized.• Nonstabilized core structure D was synthesized for the first time
by Edwin Vedejs et al.
NO NH
OH
OC(O)NH2OH
R
FR66979 R = CH2OHFR900482 R = CHO
N
OR
NR’
aziridinomitosenes
N
Y
NR’
O
N
OC(O)NH2
NH
OH
RN
OC(O)NH2
NR’
OH
H3C
MeO
OHR’ = H, Me
A B
C D
N
CO2Et
N
SnBu3
CPh3
NH
CO2Et
N
SnBu3
CPh3MsO
+
NaHMDSTHF/DMPU
47% yield
Li-Sn exchange
N
NCPh3
Li
OOEt
N
CO2Et
NCPh3
never higher than 15% yield
Aziridinomitosenes: Deuterium as a removable blocking group
Vedejs, E. J. Am. Chem. Soc. 2002, 124, 748-749.
N
CO2Et
N
SnBu3
CPh3
H
1. MeLi, -65 ºC2. EtOD
N
CO2Et
N
SnBu3
CPh3
DN
CO2Et
N
D
CPh3
D
N
CO2Et
NCPh3
DH+ +
55 : 36 : 9tetracyclic : tricyclic = 1 : 10
1. PhLi, -78 ºC2. EtOD
N
CO2Et
N
SnBu3
CPh3
D(minor)
2-indolyl lithiaiton
MeLi, -65 ºC
(major)Li-Sn
exchange
MeLi-65 ºC
N
CO2Et
N
Li
CPh3
D
N
CO2Et
N
SnBu3
CPh3
LiN
CO2Et
N
SnBu3
CPh3
HN
CO2Et
N
H
CPh3
H+
5% 17%
N
CO2Et
NCPh3
D
LiEtOH
N
CO2Et
NCPh3
HD
78%tetracyclic : tricyclic = 3.5 : 1
Aziridinomitosenes: Deuterium as a removable blocking group
Vedejs, E. J. Am. Chem. Soc. 2002, 124, 748-749.
N
CO2Et
N
SnBu3
CPh3
H
1. PhLi, -78 ºC2. EtOD3. MeLi, -65 ºC4. EtOH
N
CO2Et
N
SnBu3
CPh3
HN
CO2Et
N
H
CPh3
H
N
CO2Et
NCPh3
HD+ +
5 : 17 : 78
Li-Sn exchange2-indolyl lithiation =
4.31
N
CO2Et
N
SnBu3
CPh3
H
1. MeLi, -65 ºC2. EtOD
N
CO2Et
N
SnBu3
CPh3
DN
CO2Et
N
D
CPh3
D
N
CO2Et
NCPh3
DH+ +
55 : 36 : 9Li-Sn exchange
2-indolyl lithiation =0.49
1
kH/kD = 8.8
Aziridinomitosenes: Deuterium as a removable blocking group
Vedejs, E. J. Am. Chem. Soc. 2002, 124, 748-749.
N
CO2Et
NCPh3
D
Li
PhSeCl
N
CO2Et
NCPh3N
CO2Et
NH
1. Et3SiH, MsOH2. iPr2NEt LiAlH4
N NCPh3
OH
80% yield65% yield 72% yield
Removing the deuterium
N
CO2Et
N
SnBu3
CPh3
H
1. PhLi, -78 ºC2. EtOD3. MeLi, -65 ºC4. EtOH
N
CO2Et
N
SnBu3
CPh3
HN
CO2Et
N
H
CPh3
H
N
CO2Et
NCPh3
HD+ +
5 : 17 : 78
Li-Sn exchange2-indolyl lithiation =
4.31
Norzoanthamine
Miyashita, M. Science 2004, 305, 495-499.
N
OO
O O
O
Me
Me
H
H
Me HMe
Me
norzoanthmine
N
Me
O
Me
OMe
Me
Me
O
O
• Isolated by Uemura et al. in 1995 from Zoanthus sp.
• Strong inhibition on the the growth of P-388 murine leukemia cell lines
and human platelet aggregation
• A promising candidate for an antiosteoporotic drug
• Stereoselectively synthesized by Masaaki Miyashita et al. in 41 steps
with an overall yield of 3.5% (an average of 92% yield each step).
N
OO
O O
O
Me
Me
H
H
Me HMe
Me
OH
H HOTBS
OMe
OTBS
Et3Si
Norzoanthamine: Deuterium KIE inhibits the [1,5]-hydrogen shift
Miyashita, M. Science 2004, 305, 495-499.
OH
H HOTBS
OOMe
OTBSTf2O
2,6-di-tBuPythen DBU
OH
H HOTBS
OMe
OTBSO
H
H H
OMe
OTBS
O
Me
Et3Si Et3Si Et3Si
+
66% yield 30% yield
OTBSH H
OTf
[1,5]-H shift
OH
H HOTBS
OOMe
OTBSTf2O
2,6-di-tBuPythen DBU
OH
H HOTBS
OMe
OTBSO
H
H H
OMe
OTBS
O
Me
Et3Si Et3Si Et3Si
+
81% yield 9% yield
OTBSD D
OTf
D D D DD
D[1,5]-D shift
kH/kD = 4.1
Norzoanthamine: Deuterium KIE inhibits the [1,5]-hydrogen shift
Miyashita, M. Science 2004, 305, 495-499.
OH
H HOTBS
OMe
OTBS
Et3Si
D D
OH
H HOH
O
O
D D
BocNO
6 steps 1. TPAP, NMO2. NaClO2
OH
H HCO2H
O
O
BocNO
6 steps
norzoanthamine
50% yieldover 8 steps
78% yield
Removing deuterium
OH
H HOTBS
OOMe
OTBS
Et3Si
D D
OH
H H
OTBS
Et3Si
O
O
1. DIBAL2. Ph3PCD3Br KHMDS, THF3. 9-BBN, THF then H2O2
OH
H H
OTBS
Et3Si
OH
OH
DD
1. (NH4)6Mo7O24 TBAC, K2CO3 H2O2, THF2. (MeO)2C=O tBuOLi, THF, HMPA then MeI
OH
H H
OTBS
Et3Si
OMe
O
DD
O
tBuOLiTHF, DMPUthen MeI
OH
H H
OTBS
Et3Si
OMe
O
DD
O
1. MeLi, Et2O2. TBSCl, DMAP
17 steps from (R)-5-methylcyclohexenone
70% yieldover 5 steps
88% yield83% yield
Introducing deuterium
Welwitindolinones
Garg. N. J. Am. Chem. Soc. 2011, 133, 15797-15799.Garg, N. J. Am. Chem. Soc. 2012, 134, 1396-1399.
NMe
OO
MeCl
MeMeR1
H
R2
N-methylwelwitndolinone C
R1 = -NCS, -NCR2 = H, OH
• Isolated in 1994 and 1999
• [4.3.1]Bicyclic framework
• Promising activity against drug-resistant cancer cells
OPivMe
O
Me
Me
OTBSMe
O
NMe
Br
HMeMe
NaNH2tBuOH
THF, 23 ºC
OTBSMe
O
NMe
HMeMe
NMe
O
MeTBSO
MeMeH
H
NMe
O
MeCl
MeMeH
H
ONMe
O
MeCl
MeMeSCN
H
O
Insertion ofisothiocyanate
NMe
O
H
ClMe
HO
OH2N
HMeMe
NMe
O
H
ClMe
HNO
O
HMeMe
AgOTf, PhI(OAc)2bathophenanthroline
CH3CN, 82 ºC
Nitrene Insertion
H H
33% yield
Welwitindolinones: Deuterium KIE improves nitrene insertion
Garg, N. J. Am. Chem. Soc. 2012, 134, 1396-1399.
NMe
O
H
ClMe
HO
OH2N
HMeMe
D1. LiEt3B-D, THF2. Cl3CC(O)NCO; K2CO3
quantitative yield
NMe
O
MeCl
MeMeH
H
OH
NMe
O
H
ClMe
HO
OH2N
HMeMe
AgOTf, PhI(OAc)2bathophenanthroline
CH3CN, 82 ºC
NMe
O
H
ClMe
HNO
O
HMeMe
R R
NMe
O
MeCl
MeMeH
H
O
+
NMe
O
H
Cl
OHMeMe
HN
O
Me
R = HR = D
33% yield60% yield
25% yield8% yield
H
kH/kD = 5.7
Welwitindolinones: Deuterium KIE improves nitrene insertion
Garg, N. J. Am. Chem. Soc. 2012, 134, 1396-1399.
NMe
O
H
ClMe
HO
OH2N
HMeMe
AgOTf, PhI(OAc)2bathophenanthroline
CH3CN, 82 ºC
NMe
O
H
ClMe
HNO
O
HMeMe
R R
NMe
O
MeCl
MeMeH
H
O
+
NMe
O
H
Cl
OHMeMe
HN
O
Me
R = HR = D
33% yield60% yield
25% yield8% yield
H
kH/kD = 5.7
NMe
O
H
ClMe
HNO
O
HMeMe
D 1. Ba(OH)2•H2O2. DMP
NMe
O
MeCl
MeMeH2N
H
O
di(2-pyridyl)-thionocarbonateDMAP
NMe
O
MeCl
MeMeSCN
H
O
NMe
O
MeCl
MeMeCN
H
O
1. HCO2H, Ac2O2. Burgess reagent
quatitative yield
77% yield
NaH��DLU
LiHMDS, air
H
H
H
NMe
O
MeCl
MeMeSCN
H
O
NMe
O
MeCl
MeMeCN
H
O
48% yield
47% yield OH
OH
Danicalipin A
Burns, N. J. Am. Chem. Soc. 2016, 138, 5150-5158.
Me OSO3-
Cl
Cl
OSO3-
Cl Cl
Cl Cl
danicalipin A
• Comprise >90% of all polar lipids in the flagellar membrane of freshwater
Ochromonas danica algae
• Two anionic sulfate moieties: one at the terminus; one near the otherwise
hydrophobic center
• Synthesized by Noah Burns et al. in 2% yield in 8 steps, which is the shortest.
Danicalipin A
Burns, N. J. Am. Chem. Soc. 2016, 138, 5150-5158.
PinBB(MIDA)
IOTBS
Cl Cl
+
4 steps15% yield
OTBSCl Cl
BOO
Cy Cy
Cl
MeCl
ClH
O
nBuLi, TFAAMe OTBS
Cl
Cl
OH
Cl
Cl Cl
75% yield
Me OSO3-
Cl
Cl
OSO3-
Cl Cl
Cl Cl
Bromochlorination - radical debrominationsequence
1. CD3OD, 12h; Me4N(Cl2Br)2. Bu3SnH, Et3B, air3. ClSO3H
danicalipin A
20% yield
Danicalipin A
Burns, N. J. Am. Chem. Soc. 2016, 138, 5150-5158.
Cl OR
Cl Cl
Me4N(Cl2Br)CH3CN
Cl OR
Cl Cl Cl
Br+
Cl O
Cl
Br
Cl
R = HR = D
21% yield44% yield
65% yield43% yield
ClH
Cl
H
ClO
H
H H
RCl Br Cl
Cl Br Cl
undesired
desired
ClH
Cl
H
ClO
H
H H
R
BrCl
H
Cl
H
ClO
H
H H
R
Br
Cl- - R-
+
desired undesired
kH/kD = 3.2
• Deuteration renders the hydrogen bonding of secondary alcohol less effective.• Bromium formation is reversible and deprotonation of the alcohol during
bromoetherification is selective determining.
Application of Deuterated Compounds
Drug development: enhance metabolic stability
Clarification of organic reaction mechanisms
Elucidation of biosynthetic routes
Total synthesis: modify reaction selectivity
Mass spectrometry internal standards
Applying Deuterium to Improve Existing Drugs
H
D
deuteration
kH
kD
OH
OH
Cytochrome P450 kH > kD
• The major metabolizing enzymes in humans belong to cytochrome P450
enzyme family.• Significant KIEs have been observed for several P450-catalyzed reactions.• Potential deuterated drug benefits:
• A reduced dosage or dosing regimen• A smaller potential for drug-drug interactions• A lower incidence of side effects
Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid M. Angew. Chem. Int. Ed. 2018, 57, 1758-1784.
Deuterium clinical drug candidates
F OH
O
D NH2
NH
OH
O
O
D3CD3C
OCD3
ND3C
H
N
N N
N
O
O
D3C
O
D D
Chemical Structure Compound Status Beneficial Deuterium Effect
Fludalnine(MK-0641)
First deuterated drug candidate to enter clinic
(1970s)
Discontinued
Reduce toxic metabolite, 3-fluorolactate
Austedo®
Deutertrabenazine(SD-809)
First deuterated drug approved (2017)
Approved
Reduce rate of active metabolite demethylation driven by CYP2D6
d6-dextromethorphan(AVP-786) Phase 3
Reduce formation of toxic metabolite by CYP2D6
d5-pentoxifylline(CT-499) Phase 2
Reduce metabolism speed; primary metabolite raising up to 3 times than
that of pentoxifylline
Sabounjian, L. A. Clin. Pharmacol. Drug Dev. 2016, 5, 314-425.Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid M. Angew. Chem. Int. Ed. 2018, 57, 1758-1784.https://www.concertpharma.com/research/documents/CTP-499ASN2014PosterFINAL14NOV2014.pdfhttps://en.wikipedia.org/wiki/Deuterated_drug#VX-561_(Vertex/Concert)
Deuterium clinical drug candidates
HN
O
HN
O
OH CD3
CD3CD3
NN
NN
D
D
NHN
NH2O
N O
D
SNH
O
O
O
O
D D
Chemical Structure Compound Status Beneficial Deuterium Effect
d9-ivacaftor(VX-561) Phase 2
Reduce rate of tert-butyl group oxidation and in vivo clearance by CYP3A4
VX-984 Phase 1Reduce aldehyde oxidase(AO)-driven
metabolism
d1-(R)-pioglitazone(DRX-065) Phase 1
Stabilize preferred R-enantiomer to obtain mitochondrial function modulation
without affected by S-isomer
d2-linoleic acid ethyl ester(RT001) Phase 1/2 Limit lipid peroxidation
Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid M. Angew. Chem. Int. Ed. 2018, 57, 1758-1784.https://www.cancer.gov/publications/dictionaries/cancer-drug/def/dna-dependent-protein-kinase-inhibitor-vx-984https://en.wikipedia.org/wiki/Deuterated_drug#VX-561_(Vertex/Concert)