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
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