Synthesis and biological evaluation of new potential inhibitors of N-acylethanolamine hydrolyzing acid amidase

N-Acylethanolamines, including N-palmitoyl-ethanolamine (PEA), are hydrolyzed to the corresponding fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH). Recently, N-acylethanolamine-hydrolyzing acid amidase (NAAA) was identified as being able to specifically hydrolyze PEA. In order to find selective and effective inhibitors of this enzyme, we synthesized and screened several amides, retroamides, esters, retroesters and carbamates of palmitic acid (1–21) and esters with C15 and C17 alkyl chains (22–27). Cyclopentylhexadecanoate (13) exhibited the highest inhibitory activity on NAAA (IC50 = 10.0 μM), without inhibiting FAAH up to 50 μM. Compound 13 may become a useful template to design new NAAA inhibitors.

Graphical abstractN-Acylethanolamine-hydrolyzing acid amidase (NAAA) specifically hydrolyzes N-palmitoylethanolamine, an anti-inflammatory mediator. We synthesized and screened several new compounds, and cyclopentylhexadecanoate (13) exhibited the highest inhibitory activity on NAAA.Figure optionsDownload full-size imageDownload as PowerPoint slide