Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

Farnesoid X receptor
(FXR) agonists are emerging as important potential
therapeutics for the treatment of nonalcoholic steatohepatitis (NASH)
patients, as they exert positive effects on multiple aspects of the
disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular
inflammation, hepatic injury, and fibrosis. While there are currently
no approved therapies for NASH, the bile acid-derived FXR agonist
obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise
in clinical studies. Previously, we described the discovery of tropifexor
(LJN452), the most potent non-bile acid FXR agonist currently in clinical
investigation. Here, we report the discovery of a novel chemical series
of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole
core from which emerged nidufexor (LMB763), a compound with partial
FXR agonistic activity in vitro and FXR-dependent
gene modulation in vivo. Nidufexor has advanced to
Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.