Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia
Autor: | Jiang Wang, Hualiang Jiang, Hong Liu, Chenglin Wu, Zhao Jing, Wang Yiping, Junhua Tong, Xi Cong |
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Rok vydání: | 2019 |
Předmět: |
Tetrahydroprotoberberine derivatives
HFD high-fat diet POCl3 phosphoryl trichloride Pharmacology CHD coronary heart disease DiI-LDL low-density lipoprotein labeled with 1 1′-dioctadecyl-3 3 3′ 3′-tetramethyl-indocarbocyanine perchlorate PCSK9 t1/2 half-life chemistry.chemical_compound 0302 clinical medicine Berberine Hyperlipidemia General Pharmacology Toxicology and Pharmaceutics 0303 health sciences hERG human ether-à-go-go related gene LDLR low-density lipoprotein receptor 030220 oncology & carcinogenesis Low-density lipoprotein AUC area under the plasma concentration−time curve Kexin lipids (amino acids peptides and proteins) MRT mean residence time CVDs cardiovascular diseases mAbs monoclonal antibodies Original article PK pharmacokinetic 03 medical and health sciences medicine Cmax maximum concentration Low-density lipoprotein cholesterol LDL-C low-density lipoprotein-cholesterol Low-density lipoprotein receptor Total cholesterol THPBs tetrahydroprotoberberine derivatives ADH autosomal dominant hypercholesterolemia 030304 developmental biology Lipid-lowering Hyperlipidemia hamster lcsh:RM1-950 Proprotein convertase medicine.disease PCSK9 expression TC total cholesterol lcsh:Therapeutics. Pharmacology FDA food and drug administration chemistry LDL receptor BBR berberine PCSK9 proprotein convertase subtilisin/kexin type 9 CL clearance F oral bioavailability Lipoprotein |
Zdroj: | Acta Pharmaceutica Sinica B, Vol 9, Iss 6, Pp 1216-1230 (2019) Acta Pharmaceutica Sinica. B |
ISSN: | 2211-3835 |
DOI: | 10.1016/j.apsb.2019.06.006 |
Popis: | 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. Graphical abstract A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Compound 22 demonstrated significant reductions of TC and LDL-C in hyperlipidemic hamsters, which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.Image 1 |
Databáze: | OpenAIRE |
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