Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist

• Published in: ACS medicinal chemistry letters 2016-06, Vol.7 (6), p.590-594
• Main Authors: Shi, Yan, Li, Jun, Kennedy, Lawrence J, Tao, Shiwei, Hernández, Andrés S, Lai, Zhi, Chen, Sean, Wong, Henry, Zhu, Juliang, Trehan, Ashok, Lim, Ngiap-Kie, Zhang, Huiping, Chen, Bang-Chi, Locke, Kenneth T, O’Malley, Kevin M, Zhang, Litao, Srivastava, Rai Ajit, Miao, Bowman, Meyers, Daniel S, Monshizadegan, Hossain, Search, Debra, Grimm, Denise, Zhang, Rongan, Harrity, Thomas, Kunselman, Lori K, Cap, Michael, Muckelbauer, Jodi, Chang, Chiehying, Krystek, Stanley R, Li, Yi-Xin, Hosagrahara, Vinayak, Zhang, Lisa, Kadiyala, Pathanjali, Xu, Carrie, Blanar, Michael A, Zahler, Robert, Mukherjee, Ranjan, Cheng, Peter T. W, Tino, Joseph A
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.6b00033

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure–activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.