A Review on Farnesoid X Receptor (FXR) Modulators Focusing on Benzimidazole Scaffold

The discovery of a mechanism by which bile acids (BAs) regulate fat synthesis by modulating the activation of the farnesoid X receptor (FXR) in the liver and intestines has highlighted the central role of BAs in triglyceride synthesis in the liver. FXR has been reported as a promising drug target for primary biliary cholangitis, metabolic-dysfunction-associated steatohepatitis, and metabolic-dysfunction-associated steatotic liver disease. A large number of FXR modulators with various chemotypes have been developed by many research groups. Although several FXR modulators are advancing into clinical trials, ongoing efforts aim to develop new FXR modulators that minimize the adverse effects associated with long-term administration. To develop drug candidates targeting FXR, various heterocyclic and/or fused heteroaromatic rings have been employed as the core and/or parts of the structures, out of which benzimidazole has been recognized as a valuable structural motif due to its synthetic accessibility and its versatility in constructing structurally diverse target molecules. Herein, we report on the development of FXR modulators incorporating benzimidazole as a fused heteroaromatic ring.