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Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors (CROSBI ID 213658)

Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija

Dražić, Tonko ; Molčanov, Krešimir ; Sachdev, Vinay ; Malnar, Martina ; Hećimović, Silva ; Patankar, Jay V. ; Obrowsky, Sascha ; Levak-Frank, Sanja ; Habuš, Ivan ; Kratky, Dagmar Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors // European journal of medicinal chemistry, 87 (2014), 722-734. doi: 10.1016/j.ejmech.2014.10.014

Podaci o odgovornosti

Dražić, Tonko ; Molčanov, Krešimir ; Sachdev, Vinay ; Malnar, Martina ; Hećimović, Silva ; Patankar, Jay V. ; Obrowsky, Sascha ; Levak-Frank, Sanja ; Habuš, Ivan ; Kratky, Dagmar

engleski

Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors

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.

β-lactam; cholesterol absorption inhibitor; hyperlipidemia; cardiovascular heart disease

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Podaci o izdanju

87

2014.

722-734

objavljeno

0223-5234

10.1016/j.ejmech.2014.10.014

Povezanost rada

Kemija, Temeljne medicinske znanosti

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