posted on 2021-04-26, 19:05authored byMichael S. Malamas, Spiro Pavlopoulos, Shakiru O. Alapafuja, Shrouq I. Farah, Alexander Zvonok, Khadijah A. Mohammad, Jay West, Nicholas Thomas Perry, Dimitrios N. Pelekoudas, Girija Rajarshi, Christina Shields, Honrao Chandrashekhar, Jodi Wood, Alexandros Makriyannis
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.