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

被引：8

作者：

Chen, Dongyin ^{[1
,2
,3
]}

Huang, Xin ^{[1
,2
]}

Zhou, Hongwen ^{[4
]}

Luo, Hanqiong ^{[1
,2
]}

Wang, Pengfei ^{[1
,2
]}

Chang, Yongzhi ^{[1
,2
]}

He, Xinyi ^{[1
,2
]}

Ni, Suiying ^{[1
,2
]}

Shen, Qingqing ^{[1
,2
]}

Cao, Guoshen ^{[1
,2
]}

Sun, Hongbin ^{[1
,2
]}

Wen, Xiaoan ^{[1
,2
]}

Liu, Jun ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, Ctr Drug Discovery, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, State Key Lab Nat Med, Ctr Drug Discovery, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Sch Pharm, Dept Med Chem, Nanjing 211166, Jiangsu, Peoples R China

[4] Nanjing Med Univ, Dept Endocrinol, Affiliated Hosp 1, Nanjing 210029, Jiangsu, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 139卷

基金：

中国国家自然科学基金;

关键词：

CETP inhibitor; Pentacyclic triterpenes; Non-HDL-C; Dyslipidemia; NON-HDL-CHOLESTEROL; 14; RANDOMIZED-TRIALS; CARDIOVASCULAR RISK; ACID-DERIVATIVES; CETP INHIBITION; STATINS; THERAPY; INFLAMMATION; EFFICACY; DISEASE;

D O I：

10.1016/j.ejmech.2017.08.012

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of pentacyclic triterpene 313-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 mu M. Among them, compound 20 (IC50 = 2.3 mu M) 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. (C) 2017 Published by Elsevier Masson SAS.

引用

收藏

页码：201 / 213

页数：13

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