Discovery of Non-Carboxylic Steroidal FXR Agonist as a Promising Preclinical Candidate for Metabolic Dysfunction-Associated Steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) presents a growing global health challenge, underscoring the need for effective therapies. Farnesoid X receptor (FXR) represents a promising therapeutic target against MASH. This study reported the rational design of a novel non-carboxylic steroidal FXR agonist, compound 27, which demonstrated effective FXR agonistic activity (TR-FRET: EC 50 = 10 ± 3 nM; Luciferase Reporter: EC 50 = 128 ± 9 nM) alongside reduced activation of the off-target receptor MRGPRX4 compared to OCA. Compound 27 exhibited high oral bioavailability in rats ( F = 70.30%) and activation of hTGR5 (HTRF: EC 50 = 1360 nM). In vivo studies confirmed its efficacy: attenuated collagen deposition in the CCl 4 -induced liver fibrosis model and improved steatosis and inflammatory foci in the MASH model. In summary, compound 27 achieves its promising efficacy and safety profile by the dual-path strategy that enhances FXR/TGR5 activity while suppressing MRGPRX4, supporting its further development as a novel therapeutic agent for MASH.