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 A
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- 作者：Jun Li ; Lawrence J. Kennedy ; Yan Shi ; Shiwei Tao ; Xiang-Yang Ye ; Stephanie Y. Chen ; Ying Wang ; Andrs S. Hernndez ; Wei Wang ; Pratik V. Devasthale ; Sean Chen ; Zhi Lai ; Hao Zhang ; Shung Wu ; Rebecca A. Sm
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：April 8, 2010
- 年：2010
- 卷：53
- 期：7
- 页码：2854-2864
- 全文大小：939K
- 年卷期：v.53,no.7(April 8, 2010)
- ISSN：1520-4804
文摘
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 PPARγ 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 PPARδ. 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.