2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2010 Apr 8;53(7):2854-64. doi: 10.1021/jm9016812.
Jun Li 1,  Lawrence J Kennedy,  Yan Shi,  Shiwei Tao,  Xiang-Yang Ye,  Stephanie Y Chen,  Ying Wang,  Andrés S Hernández,  Wei Wang,  Pratik V Devasthale,  Sean Chen,  Zhi Lai,  Hao Zhang,  Shung Wu,  Rebecca A Smirk,  Scott A Bolton,  Denis E Ryono,  Huiping Zhang,  Ngiap-Kie Lim,  Bang-Chi Chen,  Kenneth T Locke,  Kevin M O'Malley,  Litao Zhang,  Rai Ajit Srivastava,  Bowman Miao,  Daniel S Meyers,  Hossain Monshizadegan,  Debra Search,  Denise Grimm,  Rongan Zhang,  Thomas Harrity,  Lori K Kunselman,  Michael Cap,  Pathanjali Kadiyala,  Vinayak Hosagrahara,  Lisa Zhang,  Carrie Xu,  Yi-Xin Li,  Jodi K Muckelbauer,  Chiehying Chang,  Yongmi An,  Stanley R Krystek,  Michael A Blanar,  Robert Zahler,  Ranjan Mukherjee,  Peter T W Cheng,  Joseph A Tino
Affiliations

Affiliation

  • 1 Metabolic Diseases Chemistry, Bristol-Myers Squibb, Building 13, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. jun.li@bms.com
PMID: 20218621 DOI: 10.1021/jm9016812
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.

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