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

文献类型：期刊论文

作者Wu, Chenglin1,3,4; Xi, Cong1,2,3; Tong, Junhua1,2,3; Zhao, Jing1,2,3; Jiang, Hualiang1,2,3; Wang, Jiang1,2,3; Wang, Yiping1,2,3; Liu, Hong1,2,3
刊名ACTA PHARMACEUTICA SINICA B
出版日期2019-11-01
卷号9期号:6页码:1216-1230
ISSN号2211-3835
关键词PCSK9 Tetrahydroprotoberberine derivatives Low-density lipoprotein cholesterol Lipid-lowering PCSK9 expression Low-density lipoprotein receptor Total cholesterol Hyperlipidemia hamster
DOI10.1016/j.apsb.2019.06.006
通讯作者Wang, Jiang(jwang@simm.ac.cn) ; Wang, Yiping(ypwang@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要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 hyperlipidemia. Among them, eight compounds exhibited excellent activities in downregulating hepatic PCSK9 expression better than berberine in HepG2 cells. In 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 (DiI-LDL) uptake assay, compared with berberine at the same concentration. Compound 22, selected for in vivo evaluation, demonstrated significant reductions of total cholesterol (TC) and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile. Further exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells. Additional results of human ether-dgo-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. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
WOS关键词DOPAMINE D-1 ; BERBERINE ; EXPRESSION ; INHIBITORS ; IDENTIFICATION ; CHOLESTEROL ; MUTATIONS ; LDLR
资助项目National Program on Key Basic Research Project of China[2015CB910304] ; National Natural Science Foundation (China)[81620108027] ; National Natural Science Foundation (China)[21632008] ; National Natural Science Foundation (China)[21402226] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program (China)[2018ZX09711002-012-007] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040213]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号WOS:000500912700010
源URL[http://119.78.100.183/handle/2S10ELR8/282059]  
专题新药研究国家重点实验室
通讯作者Wang, Jiang; Wang, Yiping; Liu, Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.China Pharmaceut Univ, Sch Pharm, Nanjing 210009, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Chenglin,Xi, Cong,Tong, Junhua,et al. Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia[J]. ACTA PHARMACEUTICA SINICA B,2019,9(6):1216-1230.
APA Wu, Chenglin.,Xi, Cong.,Tong, Junhua.,Zhao, Jing.,Jiang, Hualiang.,...&Liu, Hong.(2019).Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia.ACTA PHARMACEUTICA SINICA B,9(6),1216-1230.
MLA Wu, Chenglin,et al."Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia".ACTA PHARMACEUTICA SINICA B 9.6(2019):1216-1230.

入库方式： OAI收割

来源：上海药物研究所

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