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.

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

“…Not surprisingly, in this series of 1,2,3-thiadiazol-4-yl substituted derivatives (8,(25)(26)(27)(28)(29), the length and the shape of the N-alkyl group had a similar effect on the inhibitory potencies against both enzymes, FAAH and MGL, as it had in the previous series. Thus, by replacing the N-n-butyl chain of 8 by N-n-hexyl (25) the inhibitory potencies toward FAAH and MGL were improved (IC 50 s; 0.019 and 11 mM, respectively).…”

“…Therefore, several FAAH inhibitors have been developed (see for review Ref. [12]), including various fatty acid derivatives [13][14][15][16][17], and non-lipid inhibitors such as a-keto heterocycles [18][19][20], carbamate derivatives [21][22][23][24][25], (thio)-hydantoins [26] and most recently, selective piperidine/piperazine ureas [27,28]. Probably, the most well-studied FAAH inhibitors are the carbamate-based 3 0 -carbamoylbiphenyl-3-yl ester (4, URB597) ( Fig.…”

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

“…Inhibition by N-alkylcarbamates is based on irreversible acylation of the active site serine [25]. Recently reported other structure families with inhibitory activity against FAAH include (thio)hydantoins [26], piperidine-and piperazine ureas [27,28], sulfonyl derivatives [29] and boronic acid derivatives [30].…”

Synthesis of 2-thioxoimidazolin-4-one and thiazolo[3,2-a]-benzimidazole derivatives from substituted maleimides

“…Dependant Kinases (CDK) inhibition in a micromolar range 3a or antileishmanial activity 3b whereas compounds 3 are Fatty Acid Amide Hydrolase (FAAH) inhibitors 4 and compounds 4 are claimed to be active for treatment of hormone refractory prostate cancer. 5 So, it is not surprising if a lot of patents have described the use of this attractive skeleton for a range of activity which cover from compounds for biological use 6 till fire retardants materials.…”