Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis

Joseph Carpenter; Gang Wu; Ying Wang; Erica M Cook; Tao Wang; Doree Sitkoff; Karen A Rossi; Kathy Mosure; Xiaoliang Zhuo; Gary G Cao; Milinda Ziegler; Anthony V Azzara; Jack Krupinski; Matthew G Soars; Bruce Alan Ellsworth; Dean A Wacker

doi:10.1021/acsmedchemlett.1c00198

Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis

ACS Med Chem Lett. 2021 Aug 5;12(9):1413-1420. doi: 10.1021/acsmedchemlett.1c00198. eCollection 2021 Sep 9.

Authors

Affiliation

¹ Departments of Small Molecule Drug Discovery, Discovery Biology, and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.

Abstract

Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.