Discovery of First-in-Class FXR and HSD17B13 Dual Modulator for the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease driven by diverse metabolic and inflammatory pathways. Farnesoid X receptor (FXR) is a promising target for MASH due to its role in bile acid and lipid metabolism, while HSD17B13 regulates liver lipid droplet homeostasis. However, the existing HSD17B13 inhibitors have several druglike property challenges due to the common phenolic structure, a key pharmacophore for the HSD17B13 inhibitor. In this study, a two-round high-throughput screening was performed to identify the FXR agonist 2 as the nonphenolic HSD17B13 inhibitor. The multiparameter structural optimization led to the discovery of dual FXR/HSD17B13 modulator 6, with high target selectivity, target tissue distribution, suitable pharmacokinetic properties, and safety profiles. Moreover, even at the lower dose, compound 6 exerted a better therapeutic effect than obeticholic acid (OCA) in multiple MASH models. With attractive pharmacological activity and safety profiles, the dual FXR/HSD17B13 modulator 6 is worthy of further evaluation as a novel anti-MASH agent.