Muccioli GG, Fazio N, Scriba GK, Poppitz W, Cannata F, Poupaert JH, WoutersJ, Lambert DM.

Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates.

J Med Chem. 2006 Jan 12;49(1):417-25.

PMID: 16392827 [PubMed - indexed for MEDLINE]

The demonstration of the essential role of fatty acid amide hydrolase (FAAH) in hydrolyzing endogenous bioactive fatty acid derivates has launched the quest for the discovery of inhibitors for this enzyme. Along this line, a set of 58 imidazolidine-2,4-dione and 2-thioxoimidazolidin-4-one derivatives was evaluatied as FAAH inhibitors. Among these compounds, 3-substituted 5,5'-diphenylimidazolidine-2,4-dione and 3-substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one derivates were previously described as CB1 cannabinoid receptor ligands. In the present study, we synthetisezed several derivatives exhibiting interesting FAAH inhibitory activity and devoid of affinity for the CB1 and CB2 cannabinoid receptors. For instance, 3-heptyl-5,5'-diphenylimidazolidine-2,4-dione and 5,5'-diphenyl-3-tetradecyl-2-thioxo-imidazolidin-4-one showed p/50 values of 5.12 and 5.94, respectively. In conclusion, it appears that event though severaal 3-substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one and 3-substituted 5,5'-diphenylimidazolidine-2,4-dione derivatives have been previously shown to behave as CB1 cannabinoid receptor ligands, appropriate substitutions of these templates can result in FAAH inhibitors devoid of affinity for the cannabinoid receptors.