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

• DOI: 10.1016/j.ejmech.2014.10.014
• Publication Date: 2014-10-09T02:03:52Z
• Authors: Tonko Dražić; Krešimir Molčanov; Vinay Sachdev; Martina Malnar; Silva Hećimović; Jay V. Patankar; Sascha Obrowsky; Sanja Levak-Frank; Ivan Habuš; Dagmar Kratky
• Keywords: β-lactam; Proton Magnetic Resonance Spectroscopy; Crystallography, X-Ray; beta-Lactams; 01 natural sciences; Madin Darby Canine Kidney Cells; Inhibitory Concentration 50; Mice; Dogs; Drug Discovery; hyperlipidemia; Animals; Humans; Cholesterol absorption inhibitor; Pharmacology; Molecular Structure; Anticholesteremic Agents; cholesterol absorption inhibitor; Organic Chemistry; β-lactam; cholesterol absorption inhibitor; hyperlipidemia; cardiovascular heart disease; Basic Medical Sciences; Hep G2 Cells; 3. Good health; 0104 chemical sciences; cardiovascular heart disease; Hyperlipidemia; Cholesterol; Cardiovascular heart disease; Original Article

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.