Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

While
several farnesoid X receptor (FXR) agonists under clinical investigation
for the treatment of nonalcoholic steatohepatitis
(NASH) have shown beneficial effects, adverse effects such as pruritus
and elevation of plasma lipids have limited their clinical efficacy
and approvability. Herein, we report the discovery and preclinical
evaluation of compound 32 (BMS-986339), a nonbile acid
FXR agonist with a pharmacologically distinct profile relative to
our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit
with a context-dependent profile that resulted in tissue-selective
effects in vivo. To our knowledge, this is the first report that demonstrates
differential induction of Fgf15 in the liver and
ileum by FXR agonists in vivo. Compound 32 demonstrated
robust antifibrotic efficacy despite reduced activation of certain
genes in the liver, suggesting that the additional pharmacology of
BMS-986318 does not further benefit efficacy, possibly presenting
an opportunity for reduced adverse effects. Further evaluation in
humans is warranted to validate this hypothesis.