Discovery of novel potent indazole-based FXR agonists via scaffold hopping for MASH treatment.

The farnesoid X receptor (FXR) plays a crucial role in regulating bile acid homeostasis, inflammation, fibrosis, as well as glucose and lipid metabolism, positioning it as a promising target for the treatment of Metabolic Associated Steatohepatitis (MASH). LMB763 (Nidufexor), a clinical-stage FXR agonist developed by Novartis, has demonstrated efficacy in alleviating hepatic steatosis, inflammation, and fibrosis in preclinical MASH models. Using LMB763 as a lead compound, a series of novel compounds were designed and synthesized via a scaffold hopping strategy. The lead compound E2 exhibited potent FXR agonist activity with an EC50 value of 0.097 ± 0.009 μM and favorable hepatic microsomal metabolic stability. Additionally, compound E2 displayed good selectivity against related nuclear receptors, including LXRα/β, PPARα/γ/δ, PXR, and TGR5. In vivo evaluation confirmed that compound E2 improved hepatic steatosis in high-fat diet (HFD)-induced MASH mouse model. These findings highlight E2 as a promising candidate for further development and provide valuable insights into the design of selective FXR agonists for MASH treatment.