Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

Logo MUG-Forschungsportal

Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Dražić, T; Molčanov, K; Sachdev, V; Malnar, M; Hećimović, S; Patankar, JV; Obrowsky, S; Levak-Frank, S; Habuš, I; Kratky, D.
Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.
Eur J Med Chem. 2014; 87(2): 722-734. [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Kratky Dagmar
Levak Sanja
Obrowsky Sascha
Patankar Jay Vasant
Sachdev Vinay
Altmetrics:

Dimensions Citations:

Plum Analytics:
Number of Figures: 13
| | | | | | | | | | | | |
Abstract:
Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe. Copyright © 2014 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Find related publications in this database (Keywords)
beta-lactam
Cholesterol absorption inhibitor
Hyperlipidemia
Cardiovascular heart disease
© Meduni Graz Impressum