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

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• 作者：Yan Shi ; Jun Li ; Lawrence J. Kennedy ; Shiwei Tao ; Andrés S. Hernández ; Zhi Lai ; Sean Chen ; Henry Wong ; Juliang Zhu ; Ashok Trehan ; Ngiap-Kie Lim ; Huiping Zhang ; 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 ; Jodi Muckelbauer ; Chiehying Chang ; Stanley R. Krystek ; Yi-Xin Li ; Vinayak Hosagrahara ; Lisa Zhang ; Pathanjali Kadiyala ; Carrie Xu ; Michael A. Blanar ; Robert Zahler ; Ranjan Mukherjee ; Peter T. W. Cheng ; Joseph A. Tino
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：7
• 期：6
• 页码：590-594
• 全文大小：289K
• 年卷期：0
• ISSN：1948-5875

文摘

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.