title: 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).
abstract: 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.
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb, Building 13, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. jun.li@bms.com
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Kennedy
authors.forename: Yan
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authors.lastname: Shi
authors.forename: Shiwei
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authors.lastname: Tao
authors.forename: Xiang-Yang
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authors.forename: Stephanie Y
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authors.lastname: Chen
authors.forename: Ying
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authors.lastname: Wang
authors.forename: Andrés S
authors.initials: AS
authors.lastname: Hernández
authors.forename: Wei
authors.initials: W
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authors.forename: Hao
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authors.lastname: Zhang
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authors.lastname: Wu
authors.forename: Rebecca A
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authors.lastname: Smirk
authors.forename: Scott A
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authors.forename: Denis E
authors.initials: DE
authors.lastname: Ryono
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.forename: Ngiap-Kie
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authors.lastname: Lim
authors.forename: Bang-Chi
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authors.initials: KM
authors.lastname: O'Malley
authors.forename: Litao
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authors.lastname: Zhang
authors.forename: Rai Ajit
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authors.lastname: Srivastava
authors.forename: Bowman
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authors.forename: Daniel S
authors.initials: DS
authors.lastname: Meyers
authors.forename: Hossain
authors.initials: H
authors.lastname: Monshizadegan
authors.forename: Debra
authors.initials: D
authors.lastname: Search
authors.forename: Denise
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authors.lastname: Grimm
authors.forename: Rongan
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authors.lastname: Zhang
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrity
authors.forename: Lori K
authors.initials: LK
authors.lastname: Kunselman
authors.forename: Michael
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authors.forename: Pathanjali
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authors.lastname: Kadiyala
authors.forename: Vinayak
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authors.lastname: Hosagrahara
authors.forename: Lisa
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authors.lastname: Zhang
authors.forename: Carrie
authors.initials: C
authors.lastname: Xu
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Li
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Muckelbauer
authors.forename: Chiehying
authors.initials: C
authors.lastname: Chang
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.forename: Michael A
authors.initials: MA
authors.lastname: Blanar
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Ranjan
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Peter T W
authors.initials: PT
authors.lastname: Cheng
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tino
mesh_terms: 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
chemical_list: C549240:2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid; D010080:Oxazoles; D047493:PPAR alpha; D005998:Glycine