Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)

The
farnesoid X receptor (FXR) is a nuclear receptor that acts
as a master regulator of bile acid metabolism and signaling. Activation
of FXR inhibits bile acid synthesis and increases bile acid conjugation,
transport, and excretion, thereby protecting the liver from the harmful
effects of bile accumulation, leading to considerable interest in
FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic
steatohepatitis. We identified a novel series of highly potent non-bile
acid FXR agonists that introduce a bicyclic nortropine-substituted
benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole
scaffold. Herein, we report the discovery of 1 (tropifexor,
LJN452), a novel and highly potent agonist of FXR. Potent in vivo
activity was demonstrated in rodent PD models by measuring the induction
of FXR target genes in various tissues. Tropifexor has advanced into
phase 2 human clinical trials in patients with NASH and PBC.