ω-Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase.
ChemMedChem
; 13(17): 1833-1847, 2018 09 06.
Article
em En
| MEDLINE
| ID: mdl-30004170
ABSTRACT
Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity relationship study of a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so-optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (Ki ) of 1-19â
µm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases-monoacylglycerol lipase and fatty acid amide hydrolase-were inhibited by ω-phthalimidoalkyl aryl ureas to a lesser extent.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ureia
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Esterol Esterase
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Inibidores Enzimáticos
Limite:
Animals
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Humans
Idioma:
En
Revista:
ChemMedChem
Ano de publicação:
2018
Tipo de documento:
Article