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

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...

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Veröffentlicht in:	ACS medicinal chemistry letters 2021-09, Vol.12 (9), p.1413-1420
Hauptverfasser:	Carpenter, Joseph, Wu, Gang, Wang, Ying, Cook, Erica M, Wang, Tao, Sitkoff, Doree, Rossi, Karen A, Mosure, Kathy, Zhuo, Xiaoliang, Cao, Gary G, Ziegler, Milinda, Azzara, Anthony V, Krupinski, Jack, Soars, Matthew G, Ellsworth, Bruce Alan, Wacker, Dean A
Format:	Artikel
Sprache:	eng
Schlagworte:	Letter
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Zusammenfassung:	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.
ISSN:	1948-5875 1948-5875
DOI:	10.1021/acsmedchemlett.1c00198