Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor α selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4- yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453)
Li J.,Metabolic Diseases Chemistry |
Kennedy L.J.,Metabolic Diseases Chemistry |
Shi Y.,Metabolic Diseases Chemistry |
Tao S.,Metabolic Diseases Chemistry |
And 43 more authors.
Journal of Medicinal Chemistry | Year: 2010
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) α agonist, with an EC50 of 10 nM for human PPARα and -410-fold selectivity vs human PPAR- 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 PPAR-. 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 PPARα ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARα in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed. © 2010 American Chemical Society.