Synthesis And Biological Evaluation Of Cholic Acid Derivatives As HMG-CoA Reductase Degraders

Cardiovascular disease is a type of common diseases with a very high incidence rate for human beings.High level of cholesterol in the blood is one of the main risk factors for cardiovascular disease.Currently,the first-line drugs used clinically to lower cholesterol levels are statin drugs as the inhibitors of HMG-Co A reductase（HMGCR）which is the key enzyme in cholesterol synthesis in the body.However,long-term use of statin drugs will lead to the compensatory high expression of HMGCR,which will gradually weaken the effects of statin drugs and increase of drug dosage and its following side effects.Through previous research by our group,we have obtained a compound as an active HMGCR promoting agent,but during the later biological activity test,it was found that this compound can also cause cholesterol accumulation in cells.Cholesterol accumulation in cells can have bad effect on the survival of nerve cells,increasing the risk of the severe neurodegenerative diseases.Therefore,the targeted development of new HMGCR decomposers that will not cause cholesterol accumulation in cells is of great significance for the development of such new drugs.In this thesis,with BA as the starting material,the basic core structure was obtained through 4,4-dimethylation and Wittig-Horner reaction.Then from this core structure,a series of new steroid compounds were synthesized.All the compounds were tested at the cell level for the activities of promoting the degradation of HMGCR and intracellular cholesterol accumulation.A series of heterocyclic derivatives,including thiazoles,pyrazoles,oxazoles,pyrimidines,pyrazines and other derivatives,were obtained by modifying the structure of A ring.The structure of D-ring side chain was also changed by introducing carboxyl and amide substituents.In addition,the carbon chain length of the side chain was adjusted.The best candidate compound B1 was obtained through cell tests with the activity of promoting the degradation of HMGCR ubiquitination(EC₅₀=0.22μM)and avoiding the accumulation of intracellular cholesterol,exhibited very good development prospects.