title: Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.
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.
authors.affiliation: Ruđer Bošković Institute, Bijenička c. 54, HR-10002 Zagreb, Croatia. Electronic address: tdrazic@irb.hr.
authors.forename: Tonko
authors.initials: T
authors.lastname: Dražić
authors.affiliation: Ruđer Bošković Institute, Bijenička c. 54, HR-10002 Zagreb, Croatia.
authors.forename: Krešimir
authors.initials: K
authors.lastname: Molčanov
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: Ruđer Bošković Institute, Bijenička c. 54, HR-10002 Zagreb, Croatia.
authors.forename: Martina
authors.initials: M
authors.lastname: Malnar
authors.affiliation: Ruđer Bošković Institute, Bijenička c. 54, HR-10002 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: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Sascha
authors.initials: S
authors.lastname: Obrowsky
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 c. 54, HR-10002 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 / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004285:Dogs; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D015394:Molecular Structure; D066244:Proton Magnetic Resonance Spectroscopy; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D047090:beta-Lactams; D002784:Cholesterol
keywords: Cardiovascular heart disease; Cholesterol absorption inhibitor; Hyperlipidemia; β-lactam