title: Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates.
abstract: 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.
authors.affiliation: 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.
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.forename: Gerhard K E
authors.initials: GK
authors.lastname: Scriba
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poppitz
authors.forename: Fabio
authors.initials: F
authors.lastname: Cannata
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Poupaert
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
mesh_terms: 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
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D000099252:Fatty Acid Amide Hydrolases