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Novel propanamides as fatty acid amide hydrolase inhibitors
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
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2017 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 136, 523-542 p.Article in journal (Refereed) Published
Abstract [en]

Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroary1)-2-(4(2-(trifluoromethyl)pyridin-4-y0amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or noncompetitive (TPA14) inhibition modes.

Place, publisher, year, edition, pages
Elsevier, 2017. Vol. 136, 523-542 p.
Keyword [en]
FAAH inhibitors, Heteroaryl propanamides, Fatty acid amide hydrolase, Endocannabinoids, Anandamide
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-137605DOI: 10.1016/j.ejmech.2017.05.033ISI: 000403993500045PubMedID: 28535469OAI: oai:DiVA.org:umu-137605DiVA: diva2:1121338
Available from: 2017-07-10 Created: 2017-07-10 Last updated: 2017-07-10Bibliographically approved

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Björklund, EmmelieCipriano, MariateresaSvensson, MonaHashemian, SanazFowler, Christopher J.
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CiteExportLink to record
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Citation style
  • apa
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  • Other style
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  • de-DE
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