Universität zu Köln

Dato, Florian M., Sheikh, Miriam, Uhl, Rocky Z., Schueller, Alexandra W., Steinkrueger, Michaela, Koch, Peter, Neudoerfl, Joerg-Martin, Guetschow, Michael, Goldfuss, Bernd ORCID: 0000-0002-1814-8818 and Pietsch, Markus (2018). omega -Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase. ChemMedChem, 13 (17). S. 1833 - 1848. WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1860-7187

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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 -phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the -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 (K-i) of 1-19m 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 hydrolasesmonoacylglycerol lipase and fatty acid amide hydrolasewere inhibited by -phthalimidoalkyl aryl ureas to a lesser extent.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dato, Florian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sheikh, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Uhl, Rocky Z. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schueller, Alexandra W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinkrueger, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Neudoerfl, Joerg-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Guetschow, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Goldfuss, Bernd UNSPECIFIED orcid.org/0000-0002-1814-8818 UNSPECIFIED Pietsch, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-173172
DOI:	10.1002/cmdc.201800388
Journal or Publication Title:	ChemMedChem
Volume:	13
Number:	17
Page Range:	S. 1833 - 1848
Date:	2018
Publisher:	WILEY-V C H VERLAG GMBH
Place of Publication:	WEINHEIM
ISSN:	1860-7187
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Organic Chemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACID AMIDE HYDROLASE; SALT-ACTIVATED LIPASE; LOW-DENSITY LIPOPROTEINS; MONOACYLGLYCEROL LIPASE; MONOGLYCERIDE LIPASE; MEDICINAL CHEMISTRY; STIMULATED LIPASE; CRYSTAL-STRUCTURE; HUMAN-MILK; ENDOCANNABINOID SYSTEM Multiple languages Chemistry, Medicinal; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17317