Four Kinds Of Targeted Drug Design,Discovery And Optimization

There are four chapters in my dissertation for Ph.D.degree.Chapter 1 and chapter 2 present the discovery,design and optimization of two kinds of anti-viral agents targeting CypA.CypA,as a kind of host factor,plays critical roles in the proliferation of various kinds of viruses via its peptidyl prolyl cis-trans isomerases activity.It assists the entrance step of EV71 as a capsid uncoating regulator and regulars the prolyl peptide isomerization of NS5A protein which is essential in the process of HCV proliferation.These relationships between CypA and viruses proliferation prompted us to screen a series of small molecular CypA inhibitors previously reported by our group and found two compounds 14-15 possessed potent anti-viral activities,which were desirably for the further study.The subsequent chemical modifications via two different kinds of strategies derived two novel classes of molecules.Among the 25 compounds(A1-4,B1-19,C1-2)in chapter 1,B2 demonstrated the most potent anti-EV71 activity in virus assay(EC50?0.37 ?M),and its CypA inhibitory mechanism has been verified further.To the best of our knowledge,compound B2 was probably the most potent small molecular anti-EV71 agent via CypA inhibitory mechanism to date.On the other hand,compound D11 was identified as the most potent anti-HCV agent(EC50=019 ?M)among the 25 derivatives(D1-12,E1-13)in chapter 2.The following studies preliminary indicated that Dllwas the prodrug of lead compound 15.More importantly,Both B2 and D11 exhibited remarkable synergistic effects in combination with other kinds of anti-viral drugs,and these research provided novel therapeutic strategies and methods for preventing virus infections.Chapter 3 depicts the discovery of a series of anti-type ? diabetes mellitus(DM)agents via a novel mechanism.Endoplasmic reticulum(ER)stress is an important cause of insulin resistance and pancreas(3 cell apoptosis and thus lead to the incidence of type ? DM.Activating transcription factor 6(ATF6)is a kind of transmembrane protein in ER which mainly control the process for restoring ER stress in unfolded protein response(UPR).Therefore,ATF6 is a potential therapeutic target for anti-type ? DM,and attracted us to discover anti-type ? DM drugs targeting ATF6.After screening and identification the lead compound 22 which showed good activity for promoting ATF6 nuclear accumulation,a series of structural modifications and biological assays were conducted.Totally,31 derivatives(25-26,F1-5,G1-15,H1-9)were obtained and the best compound H1 was identified which demonstrated potent activities of insulin signaling pathway sensitization and hepatic glucose output inhibition.Furthermore,the result of animal experiment showed that H1 could significantly improve glucose homeostasis in vivo,and can be regard as a potential therapeutic agent for anti-type ? DM.Chapter 4 concerns the development of PDE2 inhibitor for preventing plumonaryarteray hypertension(PH).PDE2 is involved in multiple physiological processes by hydrolyzing two intracellular second messengers cAMP and cGMP.Recent researches have demonstrated that PDE2 is closely related with the development of PH.Besides,an X-ray crystal structure study of PDE2 in complex with its inhibitor showed its unique binding mode which could improve the inhibitor selectivity for PDE2.These researches provide vast potential for future development of novel anti-PH drugs targeting PDE2.In this chapter,we discovered an old drug clofarabine possessed good PDE2 inhibition activity which was selected as the lead for further chemical modifications.Totally,31 derivatives(29-32,I1-6,Jl-5,K1-16)were synthesized,and two potent PDE2 inhibitors K6,K16 were identified with IC50 values of 0.387 ?M and 0.334 ?M,respectively.Moreover,the preliminary SAR was summarized which was useful for directing the further modification and the remaining studies are currently in progress.