title: Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.
abstract: The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.
authors.affiliation: Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia. Electronic address: tdrazic@irb.hr.
authors.forename: Tonko
authors.initials: T
authors.lastname: Dražić
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sachdev
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Leopold
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.affiliation: Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia.
authors.forename: Martina
authors.initials: M
authors.lastname: Malnar
authors.affiliation: Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia.
authors.forename: Silva
authors.initials: S
authors.lastname: Hećimović
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
authors.affiliation: Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Habuš
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria. Electronic address: dagmar.kratky@medunigraz.at.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism / Q000493:pharmacokinetics*; D004285:Dogs; D000069438:Ezetimibe / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D013329:Structure-Activity Relationship; D014316:Tritium; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D047090:beta-Lactams; D014316:Tritium; D002784:Cholesterol; D000069438:Ezetimibe
keywords: Cardiovascular heart disease; Cholesterol absorption inhibitor; Hyperlipidemia; β-Lactam