Search for N-Acylethanolamine acid amidase (NAAA) inhibitors continues

The group of professor Piomelli is engaged in finding specific inhibitors for the enzyme N-Acylethanolamine acid amidase (NAAA).  (NAAA) is a lysosomal enzyme involved in the degradation of fatty acid ethanolamides (FAEs), a family of endogenous lipid signaling molecules that includes palmitoylethanolamide (PEA).

His group disclosed two potent and selective NAAA inhibitors:

1. the compound ARN077 (5-phenylpentyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate) and

2. the compound ARN726 (4-cyclohexylbutyl-[(S)-2-oxoazetidin-3-yl]carbamate).

The first molecule is active in vivo by topical administration in rodent models of hyperalgesia and allodynia, while the second inhibitor has more general anti-inflammatory effects in mouse models of lung inflammation.

Meanwhile a number of derivatives of ARN726 are also synthesized.

One of these molecules is believed to be a useful new tool to identify activated NAAA both in vitro and in vivo and to investigate the physiological and pathological roles of this enzyme.

Specific inhibition of these enzymes so far have not generated useful molecules, due to side effects. Therfore pure PEA remains the state of the art in the clinic for the coming years.


Romeo E, Ponzano S, Armirotti A, Summa M, Bertozzi F, Garau G, Bandiera T, Piomelli D. Activity-Based Probe for N-Acylethanolamine Acid Amidase. ACS Chem Biol. 2015 Jun 23.

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