Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453).
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.
Li
Jun
J
Metabolic Diseases Chemistry, Bristol-Myers Squibb, Building 13, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. jun.li@bms.com
Kennedy
Lawrence J
LJ
Shi
Yan
Y
Tao
Shiwei
S
Ye
Xiang-Yang
XY
Chen
Stephanie Y
SY
Wang
Ying
Y
Hernández
Andrés S
AS
Wang
Wei
W
Devasthale
Pratik V
PV
Chen
Sean
S
Lai
Zhi
Z
Zhang
Hao
H
Wu
Shung
S
Smirk
Rebecca A
RA
Bolton
Scott A
SA
Ryono
Denis E
DE
Zhang
Huiping
H
Lim
Ngiap-Kie
NK
Chen
Bang-Chi
BC
Locke
Kenneth T
KT
O'Malley
Kevin M
KM
Zhang
Litao
L
Srivastava
Rai Ajit
RA
Miao
Bowman
B
Meyers
Daniel S
DS
Monshizadegan
Hossain
H
Search
Debra
D
Grimm
Denise
D
Zhang
Rongan
R
Harrity
Thomas
T
Kunselman
Lori K
LK
Cap
Michael
M
Kadiyala
Pathanjali
P
Hosagrahara
Vinayak
V
Zhang
Lisa
L
Xu
Carrie
C
Li
Yi-Xin
YX
Muckelbauer
Jodi K
JK
Chang
Chiehying
C
An
Yongmi
Y
Krystek
Stanley R
SR
Blanar
Michael A
MA
Zahler
Robert
R
Mukherjee
Ranjan
R
Cheng
Peter T W
PT
Tino
Joseph A
JA
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D064420:Drug-Related Side Effects and Adverse Reactions; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000187:drug effects
C549240:2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid; D010080:Oxazoles; D047493:PPAR alpha; D005998:Glycine