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 CB(1) cannabinoid receptor ligands. In the present study, we synthesized several derivatives exhibiting interesting FAAH inhibitory activity and devoid of affinity for the CB(1) and CB(2) 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 CB(1) cannabinoid receptor ligands, appropriate substitutions of these templates can result in FAAH inhibitors devoid of affinity for the cannabinoid receptors.
Muccioli
Giulio G
GG
Unité de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université catholique de Louvain, Avenue E. Mounier 73, UCL-CMFA 7340, B-1200 Bruxelles, Belgium.
Fazio
Nicola
N
Scriba
Gerhard K E
GK
Poppitz
Wolfgang
W
Cannata
Fabio
F
Poupaert
Jacques H
JH
Wouters
Johan
J
Lambert
Didier M
DM
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D000099252:Fatty Acid Amide Hydrolases