Discovery of the first-in-class highly potent FXR/HSD17B13 dual modulator for the treatment of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic disease driven by multiple pathological mechanisms. We previously reported the first dual FXR/HSD17B13 modulator 1 based on the synergistic effects of FXR and HSD17B13 on MASH. However, the carboxylic acid fragment of compound 1 might cause the poor membrane permeability. To explore the non-carboxylic acid modulators, we performed the design strategy to introduce the bioisostere of carboxylic acid, which led to the discovery of the first non-carboxylic acid dual FXR/HSD17B13 modulator 10 (FXR EC50: 79 nM; HSD17B13 IC50: 180 nM). In WD + CCl4 co-induced MASH model, compound 10 significantly alleviated fatty liver in a dose-dependent manner, and the therapeutic effect is comparable to that of obeticholic acid (20 mg/kg) at the same dose. Moreover, compound 10 regulated the multiple pathological mechanisms of MASH, including the lipid metabolism, inflammation and fibrosis. With the attractive results, the dual FXR/HSD17B13 modulator 10 is worthy of further assessment as a novel anti-MASH agent.