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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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(9):722-734
Doi: 10.1016/j.ejmech.2014.10.014
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- Führende Autor*innen der Med Uni Graz
- Kratky Dagmar
- Co-Autor*innen der Med Uni Graz
- Levak Sanja
- Obrowsky Sascha
- Patankar Jay Vasant
- Sachdev Vinay
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- 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 (using NLM MeSH Indexing)
- Animals -
- Anticholesteremic Agents - chemistry
- Anticholesteremic Agents - pharmacology
- Cholesterol - metabolism
- Crystallography, X-Ray -
- Dogs -
- Hep G2 Cells -
- Humans -
- Inhibitory Concentration 50 -
- Madin Darby Canine Kidney Cells -
- Mice -
- Molecular Structure -
- Proton Magnetic Resonance Spectroscopy -
- beta-Lactams - chemistry
- beta-Lactams - pharmacology
- Find related publications in this database (Keywords)
- beta-lactam
- Cholesterol absorption inhibitor
- Hyperlipidemia
- Cardiovascular heart disease