Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia.
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
Journal
Acta pharmaceutica Sinica. B
ISSN: 2211-3835
Titre abrégé: Acta Pharm Sin B
Pays: Netherlands
ID NLM: 101600560
Informations de publication
Date de publication:
Nov 2019
Nov 2019
Historique:
received:
28
03
2019
revised:
11
06
2019
accepted:
12
06
2019
entrez:
24
12
2019
pubmed:
24
12
2019
medline:
24
12
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31867167
doi: 10.1016/j.apsb.2019.06.006
pii: S2211-3835(19)30426-5
pmc: PMC6900552
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1216-1230Informations de copyright
© 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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