Design And Synthesis Of Heterocyclic Substituted Aromatic Ether PDE4B Inhibitors

Phosphodiesterase(PDE)is one of the most important hydrolytic enzyme family in vivo.PDE hydrolyzes the second messenger cyclic adenosine monophosphate(cAMP)and cyclic guano sine monophosphate(cGMP),regulating their intracellular concentrations,and thus exert its role in the organisms.Phosphodiesterase 4(PDE4)is a sub-family of PDE which pecifically hydrolyzes cAMP.Its inhibitors have important medical value in the treatment of chronic inflammation,depression,asthma and parkinson’s disease.However,these inhibitors always show significant side effects such as nausea,dizziness,vomiting and so on.In order to solve this problem,it is urgent to develop new phosphodiesterase inhibitors.In this paper,we firstly reviewed the structures of phosphodiesterase 4 as well as its inhibitors,followed by the structure-activity relationship studies on the naphthyridone PDE4 inhibitors.Based on these work,we designed and synthesized a series of novel heterocyclic-substituted di aryl ether PDE4 inhibitors.Molecular docking studies have shown that these molecules can effectively bind to the active site of PDE4B receptor.The research work presented in this paper will provides the basis for further research and development of the related PDE4 inhibitors.The thesis consists of four chapters,which are described as follows.In the first chapter,typical family members of PDEs and the application of specific inhibitors of these enzymes are briefly reviewed.Then,the catalytic domain of PDE4 enzyme and the interaction mode between the PDE4 receptor and its hydrolyzed product AMP were introduced.Finally,the structure and activity of PDE4 specific inhibitors were reviewed.In the second chapter,the 3D quantitative structure-activity relationship(QSAR)of 50 naphthalidones derivatives as PDE4 inhibitors was studied.Firstly,initial naphthyridones were selected from literature and their 3D structures were constructed by chemical graphic software.Then,we use various methods to analyze the superposition of these molecules.Then comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)are used to analyze the superposition model,and cross validation coefficient(Q2)and correlation coefficient(R2)are used to judge the prediction and correlation of the model.Based on the analysis on the electrostatic field,the stereo field and the hydrophobic field in the 3D isoelectric map,it is found that increasing the size of substituents at the R2 site of the compound,or introducing hydrophilic polar groups on benzene ring will help to improve the inhibitory activity against PDE4.These work provide the basis for the subsequent design of PDE4 inhibitors molecules.In the third chapter,staring from the existing structure-activity relationships of naphthyridones,a series of diarylethene heterocycles compounds were designed and synthesized by molecular skeleton migration.Synthesis of the target compounds was carried out by performing Ullman-like coupling and Suzuki coupling reactions.In order to improve the yield of target compounds,the reaction conditions were optimized.The structures of these compounds were characterized by 1H NMR,13C NMR,and elemental analysis.Finally,molecular docking method was used to simulate the binding of these compounds with PDE4 receptor.The binding mode analysis showed that these compounds could bind to PDE4B enzyme well.In the fourth chapter,the content of this paper is briefly summarized.Based on these work,the future development of PDE4B specific inhibitors is prospected.