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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Published inACS medicinal chemistry letters Vol. 12; no. 9; pp. 1413 - 1420
Main Authors 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 Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 09.09.2021
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
FGF15
azaspiro[3.5]nonene
spirocycle
Farnesoid X receptor (FXR)
Nuclear hormone receptor (NHR)
CYP7a1
Nonalcoholic steatohepatitis (NASH)
SIGNAL
ITCH
SERIES
ANALOGS
FARNESOID-X-RECEPTOR
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Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.1c00198