Design, Synthesis And Evaluation Of Phospholipid Transfer Protein Inhibitors

Atherosclerosis is the most frequent underlying cause of cardiovascular disease and cerebrovascular disease and is the leading cause of death in industrialized nations. With developing of economy and society in China, the incidence of atherosclerosis is increasing remarkably. The pathogenesis of atherosclerosis is very complicated. Among many risk factors, lipid abnormality is the most important effect factor. The clinical manifests of dyslipidemia are high levels of low density lipoprotein cholesterol (LDLc) and / or low levels of high density lipoprotein cholesterol (HDLc).Phospholipid transfer protein (PLTP) and Cholesteryl ester transfer protein (CETP), both belonging to the same protein family, are both important modulators of HDL. Torcetrapib (Pfizer), a CETP inhibitor, can raise levels of HDL cholesterol and now is developing actively in phase III clinical trial for atherosclerosis prevention and treatment by combined with Atorvastatin.The results of the study on mice with stable over-expression of human PLTP and mice with PLTP gene knock-out and the study of epidemiology had shown that PLTP inhibitors have the potentiality as a new drug target to prevent and treat atherosclerosis. Until now, there is no PLTP inhibitor being published as a lead for drug design, this project takes the hint compound found by our project group as a lead and designes some novel target compounds with combination of traditional drug design and structure-based drug design.By now, twenty-four target compounds were synthesized and structurally confirmed by ¹H-NMR MS. The target compounds were evaluated in vitro for inhibition against PLTP and CETP. Radiolabeled method were used to measure PLTP inhibition . It has been shown that six compounds have remarkable PLTP inhibitory effects with IC₅₀ ranging from 20 to 90μM. It is found that compound #16 #17 #18 have the best activities against PLTP with IC₅₀ 20μM ,which are essentially the same as the most potent PLTP selective inhibitor with IC₅₀ 15μM found by Dr.GUO in the world, and they have remarkable PLTP selective inhibitory effect and IC₅₀ ranging from 25 to 90μM; #22 have the best activities against CETP with IC₅₀ 25μM, particularly ,CETP selective inhibitors are first found in this project.The structure-activity relationships(SAR) of the PLTP inhibitory activity of the target compounds were investigated. The SAR could guide molecular design of PLTP and CETP inhibitor in the next step.