Inhibitors of oleamide hydrolase

Details Inhibitors of oleamide hydrolase Inhibitors of oleamide hydrolase

C - Chemistry, Metallurgy

07

C

C07C 259/06 (2006.01) A61K 31/11 (2006.01) A61K 31/12 (2006.01) A61K 31/15 (2006.01) A61K 31/16 (2006.01) A61K 31/215 (2006.01) A61K 31/231 (2006.01) A61K 31/655 (2006.01) C07C 45/45 (2006.01) C07C 45/63 (2006.01) C07C 47/21 (2006.01) C07C 49/227 (2006.01) C07C 59/42 (2006.01) C07C 69/716 (2006.01) C07C 69/738 (2006.01) C07C 233/09 (2006.01) C07C 235/28 (2006.01) C07C 235/76 (2006.01) C07C 243/30 (2006.01) C07C 245/14 (2006.01)

Patent

CA 2258764

Inhibitors of oleamide hydrolase, responsible for the hydrolysis of an endogenous sleep-inducing lipid (1, cis-9-octadecenamide) were designed and synthesized. The most potent inhibitors possess an electrophilic carbonyl group capable of reversibly forming a (thio) hemiacetal or (thin) hemiketal to mimic the transition state of a serine or cysteine protease catalyzed reaction. In particular, the tight binding .alpha.-keto ethyl ester 8 (1.4 nM) and the trifluoromethyl ketone inhibitor 12 (1.2 nM) were found to have exceptional inhibitory activity. In addition to the inhibitory activity, some of the inhibitors displayed agonist activity which resulted in the induction of sleep in laboratory animals.

L'invention porte sur la conception et la synthèse d'inhibiteurs de l'oléamide hydrolase responsables de l'hydrolyse d'un lipide endogène provoquant le sommeil (1, cis-9-octadécènamide). Les inhibiteurs les plus puissants possèdent un groupe carbonyle électrophile capable de constituer de façon réversible un (thio) hémi-acétal ou (thio) hémi-cétal simulant l'état de transition d'une réaction catalysée par la sérine ou cystéine protéase. Il a été découvert en particulier que le alpha -céto-éthyl ester 8 (1,4 nM) à liaison renforcée et l'inhibiteur trifluorométhyl cétone 12 (1,2 nM) avaient une activité inhibitrice exceptionnelle. Outre leur activité inhibitrice, certains des inhibiteurs ont montré une activité agoniste ayant pour résultat d'induire le sommeil chez des animaux de laboratoire.

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