Discovery of novel 1-(4-aminophenylacetyl)piperidine derivatives as FXR partial agonists for the potential treatment of metabolic dysfunction-associated steatohepatitis.

Farnesoid X receptor (FXR), a nuclear receptor, plays an important role in regulating metabolic dysfunction-associated steatohepatitis (MASH). However, clinical studies have demonstrated severe side effects in patients treated with FXR full agonists, underscoring the need for partial agonists that can modulate FXR activity in a more controlled manner. Such partial agonists could provide effective MASH treatment while minimizing adverse effects. Herein, we report compound V15, a potent and selective FXR partial agonist featuring a 1-(4-aminophenylacetyl)piperidine scaffold. V15 demonstrates an EC50 value of 0.67 ± 0.08 nM (81.3 % maximum efficacy vs obeticholic acid). Additionally, V15 dose-dependently reduces steatosis and lowers TG levels in HepG2 cells. Significantly, V15 ameliorates high-fat and high-sugar diet-induced MASH in mice by mitigating hepatic steatosis, inflammation, and fibrosis. It also protects against α-naphthyl isothiocyanate-induced liver injury. Notably, V15 exhibits good target selectivity and an acceptable safety profile. These findings suggest that the novel FXR partial agonist V15 represents a promising candidate for the treatment of MASH.