Design,synthesis,and biological evaluation of novel tetrahydroprotoberberine derivatives(THPBs) as proprotein convertase subtilisin/kexin type 9(PCSK9)modulators for the treatment of hyperlipidemia

作     者：Chenglin Wu Cong Xi Junhua Tong Jing Zhao Hualiang Jiang Jiang Wang Yiping Wang Hong Liu 

作者机构：State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of PharmacyChina Pharmaceutical UniversityNanjing 210009China University of Chinese Academy of SciencesBeijing 100049China 

基　　金：the funds from National Program on Key Basic Research Project of China(2015CB910304) the National Natural Science Foundation(81620108027,21632008,and 21402226,China) National Science&Technology Major Project Key New Drug Creation and Manufacturing Program(2018ZX09711002-012-007,China) the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040213)for financial support 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2019年第9卷第6期

页      码：1216-1230页

摘      要：Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol(LDL-C).A novel series of tetrahydroprotoberberine derivatives(THPBs)were designed,synthesized,and evaluated as PCSK9 modulators for the treatment of *** them,eight compounds exhibited excellent activities in downregulatinghepatic PCSK9 expression better than berberine in HepG2 *** addition,five compounds 15,18,22,(R)-22,and(S)-22 showed better performance in the low-density lipoprotein,labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethyl-indocarbocyanine perchlorate(Dil-LDL)uptake assay,compared with berberine at the same *** 22,selected for in vivo evaluation,demonstrated significant reductions of total cholesterol(TC)and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic *** exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 *** results of human ether-ago-go related gene(hERG)inhibition assay indicated the potential druggability for compound 22,which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.

主 题 词：PCSK9 Tetrahydroprotoberberine derivatives Low-density lipoprotein cholesterol Lipid-lowering PCSK9 expression Low-density lipoprotein receptor Total cholesterol Hyperlipidemia hamster 

学科分类：1008[医学-中药学类] 1006[医学-中西医结合类] 100602[100602] 10[医学] 

核心收录：

D　O　I：10.1016/j.apsb.2019.06.006

馆 藏 号：203823318...