designsynthesisandbiologicalevaluationofnoveltetrahydroprotoberberinederivativesthpbsasproproteinconvertasesubtilisinkexintype9pcsk9modulatorsforthetreatmentofhyperlipidemia
文献类型：期刊论文
| 作者 | Wu Chenglin; Xi Cong; Tong Junhua; Zhao Jing ; Jiang Hualiang; Wang Jiang; Wang Yiping; Liu Hong
|
| 刊名 | actapharmaceuticasinicab
 |
| 出版日期 | 2019 |
| 卷号 | 9期号:6页码:1216 |
| ISSN号 | 2211-3835 |
| 关键词 | DOPAMINE D-1 BERBERINE EXPRESSION INHIBITORS IDENTIFICATION CHOLESTEROL MUTATIONS LDLR PCSK9 Tetrahydroprotoberberine derivatives Low-density lipoprotein cholesterol Lipid-lowering PCSK9 expression Low-density lipoprotein receptor Total cholesterol Hyperlipidemia hamster |
| DOI | 10.1016/j.apsb.2019.06.006 |
| 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. |
| 资助项目 | [National Program on Key Basic Research Project of China] ; [National Natural Science Foundation (China)] ; [National Science & Technology Major Project Key New Drug Creation and Manufacturing Program (China)] ; [Strategic Priority Research Program of the Chinese Academy of Sciences] |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/280752]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 中国科学院上海药物研究所 |
| 推荐引用方式 GB/T 7714 | Wu Chenglin,Xi Cong,Tong Junhua,et al. designsynthesisandbiologicalevaluationofnoveltetrahydroprotoberberinederivativesthpbsasproproteinconvertasesubtilisinkexintype9pcsk9modulatorsforthetreatmentofhyperlipidemia[J]. actapharmaceuticasinicab,2019,9(6):1216. |
| APA | Wu Chenglin.,Xi Cong.,Tong Junhua.,Zhao Jing.,Jiang Hualiang.,...&Liu Hong.(2019).designsynthesisandbiologicalevaluationofnoveltetrahydroprotoberberinederivativesthpbsasproproteinconvertasesubtilisinkexintype9pcsk9modulatorsforthetreatmentofhyperlipidemia.actapharmaceuticasinicab,9(6),1216. |
| MLA | Wu Chenglin,et al."designsynthesisandbiologicalevaluationofnoveltetrahydroprotoberberinederivativesthpbsasproproteinconvertasesubtilisinkexintype9pcsk9modulatorsforthetreatmentofhyperlipidemia".actapharmaceuticasinicab 9.6(2019):1216. |
入库方式： OAI收割
来源：上海药物研究所
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