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

Dražić, Tonko; Molčanov, Krešimir; Sachdev, Vinay; Malnar, Martina; Hećimović, Silva; Patankar, Jay V.; Obrowsky, Sascha; Levak-Frank, Sanja; Habuš, Ivan; Kratky, Dagmar (2014) Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors. European Journal of Medicinal Chemistry, 87 . pp. 722-734. ISSN 0223-5234

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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.

Item Type: Article
Uncontrolled Keywords: β-lactam; cholesterol absorption inhibitor; hyperlipidemia; cardiovascular heart disease
Subjects: BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions: Division of Molecular Medicine
Division of Physical Chemistry
Projects:
Project titleProject leaderProject codeProject type
Amino-beta-laktami - intermedijari u sintezi biološki interesantnih spojeva[70961] Ivan Habuš098-0982915-2948MZOS
Mehanizam djelovanja kolesterola u nastanku Alzheimerove bolesti[187522] Silva Katušić Hećimović098-0982522-2525MZOS
Depositing User: Martina Malnar
Date Deposited: 13 May 2015 15:20
Last Modified: 13 May 2015 15:20
URI: http://fulir.irb.hr/id/eprint/1925
DOI: 10.1016/j.ejmech.2014.10.014

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