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ID: ALA4834430
Journal: J Med Chem
Title: Design and Structure-Activity Relationships of Isothiocyanates as Potent and Selective N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibitors.
Authors: Malamas MS, Pavlopoulos S, Alapafuja SO, Farah SI, Zvonok A, Mohammad KA, West J, Perry NT, Pelekoudas DN, Rajarshi G, Shields C, Chandrashekhar H, Wood J, Makriyannis A.
Abstract: N-Acylethanolamines are signaling lipid molecules implicated in pathophysiological conditions associated with inflammation and pain. N-Acylethanolamine acid amidase (NAAA) favorably hydrolyzes lipid palmitoylethanolamide, which plays a key role in the regulation of inflammatory and pain processes. The synthesis and structure-activity relationship studies encompassing the isothiocyanate pharmacophore have produced potent low nanomolar inhibitors for hNAAA, while exhibiting high selectivity (>100-fold) against other serine hydrolases and cysteine peptidases. We have followed a target-based structure-activity relationship approach, supported by computational methods and known cocrystals of hNAAA. We have identified systemically active inhibitors with good plasma stability (t1/2 > 2 h) and microsomal stability (t1/2 ∼ 15-30 min) as pharmacological tools to investigate the role of NAAA in inflammation, pain, and drug addiction.
CiteXplore: 33900772