Discovery of pentacyclic triterpene 3β-ester derivatives as a new class of cholesterol ester transfer protein inhibitors

摘要

Abstract A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In?vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with IC 50 s less than 10?μM. Among them, compound 20 (IC 50 ?=?2.3?μM) had the most potent biological activity, and effectively ameliorated plasma lipid levels of human adipose tissue specific CETP transgenic (ap2-CETPTg) mice and guinea pigs. Additional safety evaluation (no blood pressure elevation in guinea pigs) and pharmacokinetics studies indicated that the potential druggability for compound 20 which is a promising lead for development of a new class of CETP inhibitors for the treatment of dyslipidemia. Graphical abstract Display Omitted Highlights ? A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of CETP inhibitors. ? The most potent compound 20 displayed an IC 50 value of 2.3?μM against CETP in vitro. ? Compound 20 effectively ameliorated plasma lipid levels of ap2-CETPTg mice and guinea pigs. ? Compound 20 has a good pharmacokinetic profile.