Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Patent
1996-06-26
1999-01-05
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
554 67, 514546, 514549, 514552, 514613, 514625, 514627, 514628, 564248, 568382, 568412, 568417, 568418, 568419, C07C23300
Patent
active
058565370
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.
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Koutek, et al., "Inhibitors of Arachidonoyl Ethanolamide Hydrolysis", J. Biol. Chem., 269:22937-22940 (1994).
Lerner, et al., "Cerebrodiene: A Brain Lipid Isolated from Sleep-Deprived Cats", Proc. Natl. Acad. Sci., USA, 91:9505-9508 (1994).
Maurelli, et al., "Two Novel Classes of Neuroactive Fatty Acid Amides. . .", FEBS Lett., 377:82-86 (1995).
Boger Dale L.
Henriksen Steven J.
Lerner Richard A.
Wong Chi-Huey
Carr Deborah D.
Killos Paul J.
Lewis Donald G.
The Scripps Research Institute
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