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

Giulio G. Muccioli, Nicola Fazio, Gerhard K E Scriba, Wolfgang Poppitz, Fabio Cannata, Jacques H. Poupaert, Johan Wouters, Didier M. Lambert

Research output: Contribution to journalArticle

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 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 p/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.

Original languageEnglish
Pages (from-to)417-425
Number of pages9
JournalJournal of Medicinal Chemistry
Volume49
Issue number1
DOIs
Publication statusPublished - 12 Jan 2006

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Hydantoins
Cannabinoid Receptor CB1
Derivatives
Cannabinoid Receptor CB2
Ligands
Cannabinoid Receptors
Essential Fatty Acids
Enzyme Inhibitors
Fatty Acids
Substitution reactions
Demonstrations
fatty-acid amide hydrolase
diphenyl

Cite this

Muccioli, G. G., Fazio, N., Scriba, G. K. E., Poppitz, W., Cannata, F., Poupaert, J. H., ... Lambert, D. M. (2006). Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates. Journal of Medicinal Chemistry, 49(1), 417-425. https://doi.org/10.1021/jm050977k
Muccioli, Giulio G. ; Fazio, Nicola ; Scriba, Gerhard K E ; Poppitz, Wolfgang ; Cannata, Fabio ; Poupaert, Jacques H. ; Wouters, Johan ; Lambert, Didier M. / Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 1. pp. 417-425.
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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 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 p/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.",
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Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates. / Muccioli, Giulio G.; Fazio, Nicola; Scriba, Gerhard K E; Poppitz, Wolfgang; Cannata, Fabio; Poupaert, Jacques H.; Wouters, Johan; Lambert, Didier M.

In: Journal of Medicinal Chemistry, Vol. 49, No. 1, 12.01.2006, p. 417-425.

Research output: Contribution to journalArticle

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T1 - Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates

AU - Muccioli, Giulio G.

AU - Fazio, Nicola

AU - Scriba, Gerhard K E

AU - Poppitz, Wolfgang

AU - Cannata, Fabio

AU - Poupaert, Jacques H.

AU - Wouters, Johan

AU - Lambert, Didier M.

PY - 2006/1/12

Y1 - 2006/1/12

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