Universität zu Köln

Dato, Florian M., Neudoerfl, Jorg-Martin, Guetschow, Michael, Goldfuss, Bernd ORCID: 0000-0002-1814-8818 and Pietsch, Markus (2020). omega-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase. Bioorganic Chem., 94. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1090-2120

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Abstract

The serine hydrolase monoacylglycerol lipase (MAGL) is involved in a plethora of pathological conditions, in particular pain and inflammation, various types of cancer, metabolic, neurological and cardiovascular disorders, and is therefore a promising target for drug development. Although a large number of irreversible-acting MAGL inhibitors have been discovered over the past years, there are only few compounds known so far which inhibit the enzyme in a reversible manner. Therefore, much effort is put into the development of novel chemical entities showing reversible inhibitory behavior, which is thought to cause less undesired side effects. To explore a wide range of chemical structures as MAGL binders, we have applied a virtual screening approach by docking small molecules into the crystal structure of human MAGL (hMAGL) and envisaged a library of 45 selected compounds which were then synthesized. Biochemical investigations included the determination of the inhibitory potency on hMAGL and two related hydrolases, i.e. human fatty acid amide hydrolase (hFAAH) and murine cholesterol esterase (mCEase). The most promising candidates from theses analyses, i.e. three w-quinazolinonylalkyl aryl ureas bearing alkyl spacers of three to five methylene groups, exhibited IC50 values of 20-41 mu M and reversible, detergent-insensitive behavior towards hMAGL. Among these compounds, the inhibitor 1-(3,5-bis(tri-fluoromethyl)phenyl)-3-(4-(4-oxo-3,4 dihydroquinazolin-2-yl)butyl)urea (96) was selected for further kinetic characterization, yielding a dissociation constant K-i = 15.4 mu M and a mixed-type inhibition with a pronounced competitive component (alpha = 8.94). This mode of inhibition was further supported by a docking experiment, which suggested that the inhibitor occupies the substrate binding pocket of hMAGL.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dato, Florian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neudoerfl, Jorg-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:38-352344
DOI:	10.1016/j.bioorg.2019.103352
Journal or Publication Title:	Bioorganic Chem.
Volume:	94
Date:	2020
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1090-2120
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; MONOGLYCERIDE LIPASE; ENDOCANNABINOID SYSTEM; ACCURATE DOCKING; MAGL; DERIVATIVES; ANALOGS; GLIDE; IDENTIFICATION; PREDICTION Multiple languages Biochemistry & Molecular Biology; Chemistry, Organic Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/35234