Substituted 2-Thioxoimidazolidin-4-ones and Imidazolidine-2,4-diones as Fatty Acid Amide Hydrolase Inhibitors Templates

The demonstration of the essential role of fatty acid amide hydrolase (FAAH) in hydrolyzing endogenous bioactive fatty acid derivatives 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 evaluated as FAAH inhibitors. Among these compounds, 3-substituted 5,5‘-diphenylimidazolidine-2,4-dione and 3-substituted 5,5‘-diphenyl-2-thioxoimidazolidin-4-one derivatives were previously described as CB1 cannabinoid receptor ligands. In the present study, we synthesized 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 (14) and 5,5‘-diphenyl-3-tetradecyl-2-thioxo-imidazolidin-4-one (46) showed pI 50 values of 5.12 and 5.94, respectively. In conclusion, it appears that even though several 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.