Design, synthesis and structure-activity relationship studies of novel partial FXR agonists for the treatment of fatty liver.

Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, while there is still no medicine available. Farnesoid X receptor (FXR) is considered as a potential target for the treatment of NAFLD, and there are several FXR agonists reached in clinical trials. Based on better safety, industry and academia are pursuing development of the partial FXR agonists. To extend the chemical space of existing partial FXR agonists, we performed a structure-activity relationship study based on previously reported partial agonist 1 by using bioisosteric strategy. All of these efforts resulted in the identification of novel partial FXR agonist 13, which revealed the best agonistic activity in this series. Notably, compound 13 significantly alleviated the hepatic steatosis and hepatic function index in methionine-choline deficient (MCD) induced db/db mice, a classical nonalcoholic steatohepatitis (NASH) model widely used in preclinical evaluation. These results suggested that partial FXR agonist 13 might be a promising lead compound worthy further researches.