Discovery of a pyrimidine-based steroidal FXR agonist for the treatment of metabolic dysfunction-associated steatotic liver disease.

Farnesoid X receptor (FXR) plays a crucial role in regulating bile acid homeostasis and is implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). Although FXR agonists can effectively alleviate the pathological features of MASH, but adverse effects, such as disruption of cholesterol homeostasis and pruritus, remain unresolved. Herein, the structure-based drug design was carried out based on obeticholic acid (OCA), resulting in a pyrimidine-based steroidal FXR agonist 10 (FXR TR-FRET EC50 = 42.2 nM, FXR luciferase reporter EC50 = 176.4 nM), which had comparable activity without activating the pruritus-related receptor hMRGPRX4 (OCA EC50 = 5.4 μM, agonist 10 EC50 > 90 μM). In LPS-induced RAW264.7 macrophage model, agonist 10 exhibited significant anti-inflammatory effect. Furthermore, 10 exhibited robust hepatoprotective activity on the ANIT-induced cholestatic model and CCl4-induced liver fibrosis model, with efficacy comparable to the positive control OCA. In a high-fat diet and CCl4-induced MASH mouse model, 10 significantly improved NAFLD activity score (NAS) and reduced liver fibrosis severity. With the above attractive results, agonist 10 as a novel and highly selective FXR agonist demonstrated excellent pharmacological activity and safety in preclinical studies, highlighting its potential as a therapeutic agent for metabolic dysfunction-associated steatotic liver disease and MASH.