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 (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 , , , ()-, and ()- 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 , selected for 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 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells. Additional results of human related gene (hERG) inhibition assay indicated the potential druggability for compound , which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.