Stefano Ponzano, Daniele Piomelli and many colleagues published an interesting paper, titel:
Synthesis and Structure␣Activity Relationship (SAR) of 2␣Methyl-4- oxo-3-oxetanylcarbamic Acid Esters, a Class of Potent N␣Acylethanolamine Acid Amidase (NAAA) Inhibitors
They start their paper by stating that the ethanolamides of long-chain fatty acids, or fatty acid ethanolamides (FAEs), are a class of bioactive lipids that serve important signaling functions in both plants and animals. PEA is such a signaling molecule.
Monounsaturated and saturated FAEs, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), regulate energy balance, pain, and infammation primarily by engaging peroxisome proliferator-activated receptor, a member of the nuclear receptor superfamily. PEA however, as a supplement, is widely available and cannot be patented. Therefore the authors are looking for new drugs capable of inhibiting N-acylethanolamine acid amidase (NAAA). NAAA preferentially hydrolyzes PEA and OEA and only a few NAAA inhibitors have been identified so far.
The derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)-biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated infammatory cells, and reduce tissue reactions to pro-infammatory stimuli. Recently, the authors disclosed a new molecule, ARN077 which is a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia.
The route into the clinic of molecules as these however will take many years. For now PEA is available and clearly without side effects. The new enzyme inhibitors created so far mostly are NOT devoid of side effects, and this issue needs to be resolved before such molecules can enter the clinic.
Source: Synthesis and Structure␣Activity Relationship (SAR) of 2␣Methyl-4- oxo-3-oxetanylcarbamic Acid Esters, a Class of Potent N␣Acylethanolamine Acid Amidase (NAAA) Inhibitors, dx.doi.org/10.1021/jm400739u | J. Med. Chem.