Open AccessDiscovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis
Author(s) -
Joseph Carpenter,
Gang Wu,
Ying Wang,
Emma N. Cook,
Tao Wang,
Doree Sitkoff,
Karen A. Rossi,
Kathy Mosure,
Xianlu Zhuo,
Gary Cao,
Milinda Ziegler,
Anthony V. Azzara,
J. Krupinski,
Matthew G. Soars,
Bruce A. Ellsworth,
Dean A. Wacker
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00198
Subject(s) - farnesoid x receptor , obeticholic acid , adme , agonist , pharmacology , in vivo , cholestasis , bile acid , chemistry , medicine , nuclear receptor , receptor , biochemistry , pharmacokinetics , biology , microbiology and biotechnology , transcription factor , gene
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.