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.

FXR; Fibrosis; Inflammation; MASH; hMRGPRX4.