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

Dongyin Chen; Xin Huang; Hongwen Zhou; Hanqiong Luo; Pengfei Wang; Yongzhi Chang; Xinyi He; Suiying Ni; Qingqing Shen; Guoshen Cao; Hongbin Sun; Xiaoan Wen; Jun Liu

doi:10.1016/j.ejmech.2017.08.012

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

Eur J Med Chem. 2017 Oct 20:139:201-213. doi: 10.1016/j.ejmech.2017.08.012. Epub 2017 Aug 4.

Authors

Dongyin Chen¹, Xin Huang², Hongwen Zhou³, Hanqiong Luo², Pengfei Wang², Yongzhi Chang², Xinyi He², Suiying Ni², Qingqing Shen², Guoshen Cao², Hongbin Sun², Xiaoan Wen⁴, Jun Liu⁵

Affiliations

¹ Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
² Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
³ Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
⁴ Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: wxagj@126.com.
⁵ Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: junliu@cpu.edu.cn.

PMID: 28802120
DOI: 10.1016/j.ejmech.2017.08.012

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 IC₅₀s less than 10 μM. Among them, compound 20 (IC₅₀ = 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.

Keywords: CETP inhibitor; Dyslipidemia; Non-HDL-C; Pentacyclic triterpenes.

MeSH terms

Animals
Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
Dose-Response Relationship, Drug
Drug Discovery*
Esters / chemical synthesis
Esters / chemistry
Esters / pharmacology*
Guinea Pigs
Humans
Mice
Mice, Transgenic
Molecular Structure
Structure-Activity Relationship
Triterpenes / chemical synthesis
Triterpenes / chemistry
Triterpenes / pharmacology*

Substances

Cholesterol Ester Transfer Proteins
Esters
Triterpenes