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-(5cyclopropyl-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.