Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-27
2002-10-08
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S241000, C514S242000, C514S243000, C514S247000, C514S248000, C514S249000, C514S255030, C514S258100, C514S269000, C514S354000, C514S355000, C514S361000, C514S363000, C514S365000, C514S367000, C514S374000, C514S375000, C514S381000, C514S383000, C514S394000, C514S399000, C514S685000
Reexamination Certificate
active
06462054
ABSTRACT:
TECHNICAL FIELD
The present invention relates to inhibitors of fatty acid hydrolase. More particularly, the invention relates to inhibitors of fatty acid hydrolase employing a heterocyclic pharmacophore.
BACKGROUND
Fatty acid amide hydrolase (FAAH), referred to as oleamide hydrolase and anandamide amidohydrolase in early studies, is an integral membrane protein that degrades fatty acid primary amides and ethanolamides including oleamide and anandamide, as illustrated in
FIG. 1
(M. P. Patricelli, et al., (1998)
Biochemistry
37, 15177-15187.D. G. Deutsch, et al., (1993)
Biochem. Pharmacol.
46, 791-796; F. Desarnaud, et al., (1995)
J. Biol. Chem.
270, 6030-6035; C. J. Hillard, et al., (1995)
Biochim. Biophys. Acta
1257, 249-256; N. Ueda, et al., (1995)
J. Biol. Chem.
270, 23823-23827; R. L. Omeir, et al., (1995)
Life Sci.
56, 1999-2005; S. Maurelli, et al., (1995)
FEBS Lett.
377, 82-86; and M. Maccarrone, et al., (1998).
J. Biol. Chem.
273, 32332-32339). The distribution of FAAH in the CNS suggests that it degrades neuromodulating fatty acid amides at their sites of action and is intimately involved in their regulation (E. A. Thomas, et al., (1997)
J. Neurosci. Res.
50, 1047-1052). FAAH hydrolyzes a wide range of oleyl and arachidonyl amides, the CB1 agonist 2-arachidonylglycerol, the related 1-arachidonylglycerol and 1-oleylglycerol, and methyl arachidonate, illustrating a range of bioactive fatty acid amide or ester substrates. (W. Lang, et al., (1999)
J. Med. Chem.
42, 896-902; S. K. Goparaju, et al., (1998)
FEBS Lett.
442, 69-73; Y. Kurahashi, et al., (1997)
Biochem. Biophys. Res. Commun.
237, 512-515; and T. Bisogno, et al., (1997)
Biochem. J.
322, 671. Di Marzo, V., T. Bisogno, et al., (1998)
Biochem. J.
331, 15-19). Although a range of fatty acid primary amides are hydrolyzed by the enzyme, FAAH appears to work most effectively on arachidonyl and oleyl substrates (B. F. Cravatt, et al., (1996)
Nature
384, 83-87; and D. K. Giang, et al., (1997)
Proc. Natl. Acad. Sci. USA
94, 2238-2242).
The important biological role of FAAH suggests a need for molecular regulators of its activity. However, only a select set of FAAH inhibitors have been disclosed. Amongst these is the potent endogenous inhibitor 2-octyl &ggr;-bromoacetoacetate, which was discovered prior to FAAH and characterized as an endogenous sleep-inducing compound (M. P. Patricelli, et al., (1998)
Bioorg. Med. Chem. Lett.
8, 613-618; and S. Torii, et al., (1973)
Psychopharmacologia
29, 65-75). After the discovery of FAAH, elaborations of 2-octyl &ggr;-bromoacetoacetate were developed and characterized as potent inhibitors of this enzyme. Moreover, subsequent inhibitors employ a fatty acid structure attached to pharmacophoric head group. The pharmacophoric head groups can generally be classified as either reversible or irreversible. Reversible inhibitors include electrophilic carbonyl moieties, e.g., trifluoromethyl ketones, &agr;-halo ketones, &agr;-keto esters and amides, and aldehydes. Irreversible inhibitors include sulfonyl fluorides and fluorophosphonates. (B. Koutek, et al., (1994)
J. Biol. Chem.
269, 22937-22940; J. E. Patterson, et al., (1996)
J. Am. Chem. Soc.
118, 5938-5945; D. L. Boger, et al., (1999)
Bioorg. Med. Chem. Lett.
9, 167-172; D. G. Deutsch, et al., (1997)
Biochem. Pharmacol.
53, 255-260. D. G. Deutsch, et al., (1997)
Biochem. Biophys. Res. Commun.
231, 217-221; and L. De Petrocellis, et al., (1997)
Biochem. Biophys. Res. Commun.
231, 82-88; and L. De Petrocellis, et al., (1998) In
Recent Advances Prostaglandin, Thromboxane, and Leukotriene Research,
Plenum Press: New York, 259-263).
SUMMARY OF INVENTION
One aspect of the invention is directed to an inhibitor of fatty acid amide hydrolase represented by the formula A—B—C . In this formula, A is an &agr;-keto heterocyclic pharmacophore for inhibiting the fatty acid amide hydrolase; B is a chain for linking A and C, said chain having a linear skeleton of between 3 and 9 atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, the linear skeleton having a first end and a second end, the first end being covalently bonded to the &agr;-keto group of A, with the following proviso: if the first end of said chain is an &agr;-carbon with respect to the &agr;-keto group of A, then the &agr;-carbon is optionally mono- or bis-functionalized with substituents selected from the group consisting of fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, and alkyl; and C is an activity enhancer for enhancing the inhibition activity of said &agr;-keto heterocyclic pharmacophore, said activity enhancer having at least one &pgr;-unsaturation situated within a &pgr;-bond containing radical selected from a group consisting of aryl, alkenyl, alkynyl, and ring structures having at least one unsaturation, with or without one or more heteroatoms, said activity enhancer being covalently bonded to the second end of the linear skeleton of B, the &pgr;-unsaturation within the &pgr;-bond containing radical being separated from the &agr;-keto group of A by a sequence of no less than 4 and no more than 9 atoms bonded sequentially to one another, inclusive of said linear skeleton.
In a preferred embodiment, said &agr;-keto heterocyclic pharmacophore is represented by the formula:
In the above formula, “het” is selected from the following group:
In a preferred mode of the above embodiment, “het” is selected from the following group:
One group of inhibitors having a particularly high activity is represented by the following structure:
In the above structure, R
1
and R
2
are independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, and alkyl; and “n” is an integer between 2 and 7.
Another aspect of the invention is directed to a process for inhibiting a fatty acid amide hydrolase. The process employs the step of contacting the fatty acid amide hydrolase with an inhibiting concentration of any of the above inhibitors represented above by the formula A—B—C.
Another aspect of the invention is directed to a process for enhancing SWS2 or REM sleep. The process employs the step of administering a therapeutically effective quantity to a patient of a fatty acid amide hydrolase inhibitors represented above by formula A—B—C.
REFERENCES:
Edwards, et al., “Design, Synthesis, and Kinetic Evaluation of a Unique Class of Elastase Inhibitors, the Peptidyl &agr;-Ketobenzoxazoles, and the X-ray Crystal Structure of the Covalent Complex between Porcine Pancreatic Elastase and Ac-Ala-Pro-Val-2-Benzoxazole”,J. Am. Chem. Soc. 114:1854-1863 (1992).
Lerner, et al., “Cerebrodiene: A Brain Lipid Isolated from Sleep-Deprived Cats”,Proc. Natl. Acad. Sci. USA 91: 9505-9508 (1994).
Koutek, et al., “Inhibitors of Arachidonoyl Ethanolamide Hydrolysis”,J. Biol. Chem. 269: 22937-22940 (1994).
Cravatt, et al., “Chemical Characterization of a Family of Brain Lipids That Induce Sleep”,Science 268: 1506-1509 (1995).
Ueda, et al., “Partial Purification and Characterization of the Porcine Brain Enzyme Hydrolyzing and Synthesizing Anandamide”,J. Biol. Chem. 270: 23823-23827 (1995).
Cravatt, et al., “Structure Determination of an Endogenous Sleep-Inducing Lipid, cis-9-Octadecenamide (Oleamide): A Synthetic Approach to the Chemical Analysis of Trace Quantities of a Natural Product”,J. Am. Chem. Soc. 118: 580-590 (1996).
Patterson, et al., “Inhibition of Oleamide Hydrolase Catalyzed Hydrolysis of the Endogenous Sleep-Inducing Lipid cis-9-Octadecenamide”,J. Am. Chem. Soc. 118:5938-5945 (1996).
Cravatt, et al., “Molecular Characterization of an Enzyme that Degrades Neuromodulatory Fatty-Acid Amides”,Nature 384: 83-87 (1996).
Petrocellis, et al., “Novel Inhibitors of Brain, Neuronal, and Basophilic Anandamide Amidohydrolase”,Biochem. Biophys. Res. Commun. 231: 82-88 (1997).
Deutsch, et al., “Fatty Acid Sulfonyl Fluorides Inhibit Anandamide Metabolism and Bind to the Cannabinoid Receptor”,Biochem. Biophys. Res. Commun. 231: 217-221 (1997).
Bisogno, et al., “Biosynthesis, Release and Degradation of
Dentz Bernard
Lewis Donald G.
The Scripps Research Institute
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