Design,Synthesis And Biological Studies Of Novel Indole-containing Compounds As Farnesoid X Receptor Agonists

Non-alcoholic fatty liver disease（NAFLD）is characterized by liver lipid accumulation,accompanied by insulin resistance.Non-alcoholic steatohepatitis（NASH）,as an inflammatory subtype of NAFLD,is closely related to poor prognosis such as liver fibrosis,cirrhosis and hepatocellular carcinoma（HCC）.It is a severe epidemic disease that affects human life and health,and it is also a disease area where treatments are severely lacking.With the"two hits"hypothesis related to the pathogenesis of NASH,the current selection of anti-NASH drug treatment targets mainly focuses on three aspects:metabolic regulation,anti-inflammatory and anti-fibrosis.Farnesoid X receptor is a member of the nuclear receptor family with bile acid as a natural ligand,which can regulate the metabolic process and homeostasis of bile acid,glucose and fat.FXR has been recognized as a target for the treatment of NASH.The clinical trial results of steroidal FXR agonists represented by obeticholic acid confirmed the anti-NASH therapeutic effect of targeting FXR,but they also showed side effects such as itching and elevated serum cholesterol.The common problems of existing small molecule FXR agonists are toxic side effects,low solubility and poor pharmacokinetic properties.By summarizing the structure-activity relationship of reported FXR agonist compounds,we found that active molecules have two obvious structural characteristics:one is that they usually have strong hydrophobic property,which is compatible with the ligand binding cavity and stabilizes the active conformation of FXR through the hydrophobic structure;the other is that there are at least two hydrogen bond donors or acceptors in the molecule,so that the ligand conformation can be fixed in the binding cavity through polar interactions.In addition,we also found that the FXR receptor binding cavity can accommodate a variety of structural frameworks with different shapes and sizes.WAY-450 is a non-steroidal small molecule FXR agonist with high activity(EC₅₀=2 n M)and high selectivity（no significant cross-reactivity with other receptors at a concentration of 10 n M）.It has been proven to produce therapeutic effects in animal models of various metabolic-related diseases such as dyslipidemia,atherosclerosis,and non-alcoholic fatty liver disease.And because of its excellent performance in lowering blood lipids,it has entered the clinical phase I study.However,the clinical trial was terminated due to non-safety issues such as solubility.Its molecular structure is highly hydrophobic and highly planar,and its water solubility is poor.Based on WAY-450,this thesis uses three drug design strategies to or try to design and synthesize active compounds with improved solubility.One is to try to prepare phosphate prodrugs by introducing polar and ionizable prodrug groups into the structure to increase the solubility of the drug;The second is to replace the original side chain connected by amide bond with rotatable side chains to reduce the planarity of the molecule;the third is to use the induced fit theory to carry out a new molecular design,and obtained indole series compounds containing two flexible side chains.In this research,39 novel target compounds have been sythesised and tested in molecular binding assay.And a novel series of indole containing compounds were found to be active.The most active compound showed EC₅₀ of 446 n M.Furter optimization may lead to more potent and selective FXR agonists towards development as anti-NASH drugs.