Title:
オレアミドヒドロラーゼ阻害剤
Document Type and Number:
Japanese Patent JP4184435
Kind Code:
B2
Abstract:
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 (thio) 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.
Inventors:
Learner Richard A
Won Hui
Bogger Dale El
Henriksen Steven Jay
Won Hui
Bogger Dale El
Henriksen Steven Jay
Application Number:
JP50355798A
Publication Date:
November 19, 2008
Filing Date:
June 26, 1997
Export Citation:
Assignee:
THE SCRIPPS RESEARCH INSTITUTE
International Classes:
A61K31/16; A61K31/08; A61K31/11; A61K31/12; A61K31/121; A61K31/15; A61K31/201; A61K31/21; A61K31/23; A61K31/231; A61K31/655; A61P25/20; A61P43/00; C07C45/45; C07C45/63; C07C47/21; C07C49/227; C07C59/42; C07C69/716; C07C69/738; C07C233/09; C07C235/28; C07C235/76; C07C243/30; C07C245/14; C07C259/06
Foreign References:
| WO1996009817A1 |
Other References:
CRAVATT, B. F., et al., Chemical Characterization of a Family of Brain Lipids That Induce Sleep, SCIENCE, 1995年, 268, pp. 1506-1509
MAURELLI, S., et al., Two novel classes of neuroactive fatty acid amides are substrates for mouse neuroblastoma 'anandamide amidohydolase' , FEBS Letters, 1995年, 377, pp. 82-86
KOUTEK, B., et al., Inhibitors of Arachidonoyl Ethanolamide Hydrolysis, THE JOURNAL OF BIOLOGICAL CHEMISTRY, 1994年, 269(37), pp. 22937-22940
BOIVIN, J., et al., A New and Efficient Synthesis of Trifluoromethyl Ketones from Carboxylic Acids. Part I., Tetrahedron, 1995年, 51(9), pp. 2573-2584
MAURELLI, S., et al., Two novel classes of neuroactive fatty acid amides are substrates for mouse neuroblastoma 'anandamide amidohydolase' , FEBS Letters, 1995年, 377, pp. 82-86
KOUTEK, B., et al., Inhibitors of Arachidonoyl Ethanolamide Hydrolysis, THE JOURNAL OF BIOLOGICAL CHEMISTRY, 1994年, 269(37), pp. 22937-22940
BOIVIN, J., et al., A New and Efficient Synthesis of Trifluoromethyl Ketones from Carboxylic Acids. Part I., Tetrahedron, 1995年, 51(9), pp. 2573-2584
Attorney, Agent or Firm:
Minoru Nakamura
Fumiaki Otsuka
Shishido Kaichi
Hideto Takeuchi
Toshio Imajo
Nobuo Ogawa
Village shrine Atsuo
Kenji Asai
Fumiaki Otsuka
Shishido Kaichi
Hideto Takeuchi
Toshio Imajo
Nobuo Ogawa
Village shrine Atsuo
Kenji Asai