Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis.
Carpenter J, Wu G, Wang Y, Cook EM, Wang T, Sitkoff D, Rossi KA, Mosure K, Zhuo X, Cao GG, Ziegler M, Azzara AV, Krupinski J, Soars MG, Ellsworth BA, Wacker DA.
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. The overall profile of compound <b>1</b> supports its continued evaluation.