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.
Joseph Carpenter  1 ,  Gang Wu  1 ,  Ying Wang  1 ,  Erica M Cook  1 ,  Tao Wang  1 ,  Doree Sitkoff  1 ,  Karen A Rossi  1 ,  Kathy Mosure  1 ,  Xiaoliang Zhuo  1 ,  Gary G Cao  1 ,  Milinda Ziegler  1 ,  Anthony V Azzara  1 ,  Jack Krupinski  1 ,  Matthew G Soars  1 ,  Bruce Alan Ellsworth  1 ,  Dean A Wacker  1
Affiliations
  • 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.
PMID: 34531950 DOI: 10.1021/acsmedchemlett.1c00198
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.

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