Design,Synthesis And Activity Evaluation Of Farnesol X Receptor Agonists

As a bile acid receptor,Farnesol X receptor(FXR)participates in various metabolisms in the body and has a related effect on liver diseases,intestinal diseases,gallbladder diseases,glucose metabolism,cancer,and kidney diseases etc.At present,there is no drug approved for the treatment of nonalcoholic fatty liver disease(NAFLD).The FXR receptor agonist Obeticholic Acid lunched in 2016 is used to treat primary biliary cholangitis and the Phase ? clinical trials of NAFLD is undergoing.It is expected to be the first drug to treat non-alcoholic steatohepatitis(NASH).But because it is a steroidal compound,there are many adverse reactions.Although non-steroidal FXR agonist compound GW4064 is very active,the toxicity caused by the benzenediene fragment led to the suspend of GW4064 in the early stage.However,there are few drugs entering clinical studies,so the development of FXR agonists of non-steroidal GW4064 analogs is of great significance.By analyzing the structure-activity relationship of the pre-FXR agonist compounds,it was found that the active center of GW4064 is mainly at two side.The structural modification can be carried out in the middle region with the intermediate benzene ring and the olefinic bond which connected the two benzene rings.In order to obtain target compounds with similar activity to GW4064,the active fragment of GW4064 should be kept and then replace the modified intermediate benzene ring and olefinic bond.In our studies,two series of new FXR agonist were designed and synthesized.The first series of target compounds focus on the modification on phenyl ring of the GW4064 and have been replaced with fragment of cyclohexane or azacycloalkyl.The second series target compounds change the olefinic bond to methyl or carbamido and with the phenyl ring unchanged.Totally,12 target compounds were prepared by coupling and Williamson reaction.The structure of target compound was confirmed by 1H-NMR,13C-NMR and HRMS.Evaluation in vitro showed that the EC50 of some compounds was very good,and some active compounds exhibited agonistic activity.According to the result of EC50 and agonistic activity,four compounds were selected for in vivo experiments.These four compounds can reduce the levels of ALT and AST in the ConA-induced acute hepatitis mice,and three of the compounds can significantly reduce the ALT and AST levels compared with control.The result of evaluation in vivo and in vitro suggested that the olefinic bond and the phenyl ring in the GW4064 could be modified.It is necessary to further modify and optimize to find a better fragment to replace olefinic bond and a substitute phenyl ring.Also further experiments should be performed to evaluate their pharmacokinetic,toxicity and physicochemical stability,which could give more data to determine or optimization FXR agonist in development.