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.
Keywords:
ADH, autosomal dominant hypercholesterolemia; AUC, area under the plasma concentration−time curve; BBR, berberine; CHD, coronary heart disease; CL, clearance; CVDs, cardiovascular diseases; Cmax, maximum concentration; DiI-LDL, low-density lipoprotein, labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate; F, oral bioavailability; FDA, food and drug administration; HFD, high-fat diet; Hyperlipidemia hamster; LDL-C, low-density lipoprotein-cholesterol; LDLR, low-density lipoprotein receptor; Lipid-lowering; Low-density lipoprotein cholesterol; Low-density lipoprotein receptor; MRT, mean residence time; PCSK9; PCSK9 expression; PCSK9, proprotein convertase subtilisin/kexin type 9; PK, pharmacokinetic; POCl3, phosphoryl trichloride; TC, total cholesterol; THPBs, tetrahydroprotoberberine derivatives; Tetrahydroprotoberberine derivatives; Total cholesterol; hERG, human ether-à-go-go related gene; mAbs, monoclonal antibodies; t1/2, half-life.