Synthesis And Screening Of Phosphodiesterase 9(PDE9A)Inhibitors Use To Treat Alzheimer's Disease

Objective Phosphodiesterase 9(PDE9)is a new target for the treatment of alzheimer's disease(AD).Its inhibitors show good prospects for the treatment of AD and had attracted wide attention of international pharmaceutical companies.The researches on PDE9 inhibitors in China is few,and the products entering clinical trials is even fewer.This subject aims at the study of the Structure-Activity Relationship of PDE9 inhibitor compounds,the design of the new PDE9 inhibitor compounds of independent intellectual property rights,and finding out the compounds of highly PDE9 inhibitory activity and put into druggability research,in order to provide a scientific basis for the continuation research of the target.Methods In order to find the ideal compound,medicinal chemistry method were used to study the structure-activity relationship on the basis of PF-04447943,the structure was divided into four parts:the Core,part A,part B and part C.Further structural modifications were performed after the new compounds were designed,synthesized and PDE9 enzymatic activity were evaluated.Results Series compounds were designed and synthesized in this project.After PDE9 enzymatic activity testing,two skeletal structure were found.Two five-membered ring modular compounds represented by compound 24 and 27 with enzymatic activity of 1-2nM,which is equivalent to PF-04447943.One four-membered ring modular compounds represented by compound 14,in vitro enzymatic activity can reach lOnM.And the further human liver microsomal stability test show 48%of 60 min remaining.It indicate that compound 14 be used as the lead compound to continuously development is acceptable.Conclusion The enzymatic inhibitory activity of PDE9 confirmed that PDE9 inhibitors have great research value as drugs for the treatment of AD.In this study,two novel skeletal compounds were found by structure-activity relationship studies which have the equal in vitro activity level of PF-04447943 and could be used as important lead compound for further studies.Stability and DMPK are taking into account to further modifications.