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

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

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 (T...

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Main Authors: Chenglin Wu, Cong Xi, Junhua Tong, Jing Zhao, Hualiang Jiang, Jiang Wang, Yiping Wang, Hong Liu
Format: Article
Language:English
Published: Elsevier 2019-11-01
Series:Acta Pharmaceutica Sinica B
Online Access:http://www.sciencedirect.com/science/article/pii/S2211383519304265
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language English
format Article
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author Chenglin Wu
Cong Xi
Junhua Tong
Jing Zhao
Hualiang Jiang
Jiang Wang
Yiping Wang
Hong Liu
spellingShingle Chenglin Wu
Cong Xi
Junhua Tong
Jing Zhao
Hualiang Jiang
Jiang Wang
Yiping Wang
Hong Liu
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
author_facet Chenglin Wu
Cong Xi
Junhua Tong
Jing Zhao
Hualiang Jiang
Jiang Wang
Yiping Wang
Hong Liu
author_sort Chenglin Wu
title Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia
title_short Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia
title_full Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia
title_fullStr Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia
title_full_unstemmed Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia
title_sort design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (thpbs) as proprotein convertase subtilisin/kexin type 9 (pcsk9) modulators for the treatment of hyperlipidemia
publisher Elsevier
series Acta Pharmaceutica Sinica B
issn 2211-3835
publishDate 2019-11-01
description 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-à-go-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. Key words: PCSK9, Tetrahydroprotoberberine derivatives, Low-density lipoprotein cholesterol, Lipid-lowering, PCSK9 expression, Low-density lipoprotein receptor, Total cholesterol, Hyperlipidemia hamster
url http://www.sciencedirect.com/science/article/pii/S2211383519304265
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spelling doaj-ad1c42434fb64a85994c9d9f7e33d78a2020-11-25T01:56:26ZengElsevierActa Pharmaceutica Sinica B2211-38352019-11-019612161230Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemiaChenglin Wu0Cong Xi1Junhua Tong2Jing Zhao3Hualiang Jiang4Jiang Wang5Yiping Wang6Hong Liu7State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding authors. Tel.: +86 21 50807042 (Hong Liu); +86 21 50806733 (Yiping Wang); +86 21 50806600 5418 (Jiang Wang).State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding authors. Tel.: +86 21 50807042 (Hong Liu); +86 21 50806733 (Yiping Wang); +86 21 50806600 5418 (Jiang Wang).State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding authors. Tel.: +86 21 50807042 (Hong Liu); +86 21 50806733 (Yiping Wang); +86 21 50806600 5418 (Jiang Wang).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-à-go-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. Key words: PCSK9, Tetrahydroprotoberberine derivatives, Low-density lipoprotein cholesterol, Lipid-lowering, PCSK9 expression, Low-density lipoprotein receptor, Total cholesterol, Hyperlipidemia hamsterhttp://www.sciencedirect.com/science/article/pii/S2211383519304265

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