Eur J Med Chem. 2017 May 12;136:523-542. doi: 10.1016/j.ejmech.2017.05.033.
[Epub ahead of print]
Deplano A1, Morgillo CM2, Demurtas M1, Björklund E3, Cipriano M3, Svensson M3, Hashemian S3, Smaldone G4, Pedone E5, Luque FJ6, Cabiddu MG7, Novellino E2, Fowler CJ3, Catalanotti B8, Onnis V1.
Abstract
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-(heteroaryl)-2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)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 non-competitive (TPA14) inhibition modes.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Anandamide; Endocannabinoids; FAAH inhibitors; Fatty acid amide hydrolase; Heteroaryl propanamides
- PMID: 28535469
- DOI: 10.1016/j.ejmech.2017.05.033