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Novel propanamides as fatty acid amide hydrolase inhibitors
Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
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2017 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 136, s. 523-542Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2017. Vol. 136, s. 523-542
Nyckelord [en]
FAAH inhibitors, Heteroaryl propanamides, Fatty acid amide hydrolase, Endocannabinoids, Anandamide
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
URN: urn:nbn:se:umu:diva-137605DOI: 10.1016/j.ejmech.2017.05.033ISI: 000403993500045PubMedID: 28535469OAI: oai:DiVA.org:umu-137605DiVA, id: diva2:1121338
Tillgänglig från: 2017-07-10 Skapad: 2017-07-10 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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Björklund, EmmelieCipriano, MariateresaSvensson, MonaHashemian, SanazFowler, Christopher J.

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Björklund, EmmelieCipriano, MariateresaSvensson, MonaHashemian, SanazFowler, Christopher J.
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