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

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

Izvornik
European journal of medicinal chemistry (0223-5234) 87 (2014); 722-734

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

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

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

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