Design and Structure-Activity Relationships of Isothiocyanates as Potent and Selective N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibitors

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 (t(1/2) > 2 h) and microsomal stability (t(1/2) similar to 15-30 min) as pharmacological tools to investigate the role of NAAA in inflammation, pain, and drug addiction.

Automated summary

N-Acylethanolamines, particularly the palmitoylethanolamide hydrolyzed by NAAA, have been studied for their role in inflammation, pain, and drug addiction. Through synthesis and structure-activity relationship studies, potent inhibitors for hNAAA have been developed with high selectivity against other enzymes. These inhibitors have been identified as pharmacological tools for investigating the role of NAAA in various physiological processes.