Synthesis, Structure-Activity, and Structure-Stability Relationships of 2-Substituted-N-(4-oxo-3-oxetanyl)N-Acylethanolamine Acid Amidase (NAAA) Inhibitors

N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator-activated receptora (PPAR-a). Compounds that feature an a-amino-b-lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti-inflammatory effects that are mediated through FAE-dependent activation of PPAR-a. We synthesized and tested a series of racemic, diastereomerically pure b-substituted a-amino-b-lactones, as either carbamate or amide derivatives, investigating the structure–activity and structure–stability relationships (SAR and SSR) following changes in b-substituent size, relative stereochemistry at the a- and b-positions, and a-amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the b-position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability.