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.