Original articles
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[J]. Acta Pharmaceutica Sinica B, 2019, 9(6): 1216-1230

Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia
Chenglin Wua,b, Cong Xia,c, Junhua Tonga,c, Jing Zhaoa,c, Hualiang Jianga,c, Jiang Wanga,c, Yiping Wanga,c, Hong Liua,c
a 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;
b School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China;
c University of Chinese Academy of Sciences, Beijing 100049, China
Abstract:
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   
Received: 2019-03-28     Revised: 2019-06-11
DOI: 10.1016/j.apsb.2019.06.006
Funds: We gratefully acknowledge 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), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040213) for financial support.
Corresponding author: Jiang Wang, Yiping Wang, Hong Liu     Email:jwang@simm.ac.cn;ypwang@simm.ac.cn;hliu@simm.ac.cn
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Chenglin Wu
Cong Xi
Junhua Tong
Jing Zhao
Hualiang Jiang
Jiang Wang
Yiping Wang
Hong Liu

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