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

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.

SUBMITTER: Carpenter J

PROVIDER: S-EPMC8436248 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Carpenter Joseph J Wu Gang G Wang Ying Y Cook Erica M EM Wang Tao T Sitkoff Doree D Rossi Karen A KA Mosure Kathy K Zhuo Xiaoliang X Cao Gary G GG Ziegler Milinda M Azzara Anthony V AV Krupinski Jack J Soars Matthew G MG Ellsworth Bruce Alan BA Wacker Dean A DA

ACS medicinal chemistry letters 20210805 9

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 <b>1</b> (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound <b>1</b> 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. Th ...[more]

PMID: 34531950

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