Design And Synthesis Of Bile Acids Receptor Farnesoid X Receptor Antagonists

As metabolites of cholesterol,bile acids not only have physiological functions such as promoting intestinal absorption and transportation of dietary lipids,but also participate in metabolic regulation as signal molecules.Farnesoid X receptor（FXR）is specifically recognized by bile acid,which plays an important role in the regulation of bile acids homeostasis and glucose and lipid metabolism.With the increasing incidence of obesity and metabolic syndrome,non-alcoholic fatty liver disease（NAFLD）has become the most common chronic liver disease worldwide.It may progress to non-alcoholic steatohepatitis（NASH）,fibrosis,and cirrhosis up to hepatocellular carcinoma（HCC）.In addition to hepatic steatosis,NAFLD patients also have symptoms such as obesity,type 2 diabetes or metabolic disorders.What is more,obesity is closely related to early liver disease leading to severe steatosis,and more than 1/4 of NAFLD patients with type 2 diabetes will develop advanced cirrhosis.FXR antagonists have shown many beneficial effects in animal models,such as improving metabolic disorders,reducing liver cholesterol,and reducing inflammation.However,currently reported FXR antagonists are mainly endogenous bile acids and some synthetic small molecule compounds.Therefore,the research of FXR antagonists can not only provide new strategies for the treatment of some diseases and avoid the side effects of agonists,but also become an important tool for the research of FXR.In this work,a series of novel FXR antagonists were designed and synthesized by mimicking endogenous bile acids by modification of natural products.By cleaving the C ring of cholesterol,we designed and synthesized a series of novel FXR antagonists.Compound F12 showed potent FXR antagonistic activity(IC₅₀=4.6μM)and down-regulated the expression of FXR downstream genes in ileum,but also affected liver.In addition,modification of dehydroepiandrosterone by similar design approach also revealed a series of compounds with FXR antagonistic activity,which has the potential for further modification.Compound D6 showed potent FXR antagonistic activity(IC₅₀=1.2μM),and could selectively down-regulated the expression of FXR downstream genes in ileum,and had no effect on liver in mice.These novel naturally active molecules provide a new starting point for further exploration of FXR antagonists as lead compounds in the treatment of metabolic diseases.