Selective neuronal nitric oxide synthase inhibitors

Details Selective neuronal nitric oxide synthase inhibitors Selective neuronal nitric oxide synthase inhibitors

2002-06-24

2004-10-12

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S152000, C548S537000, C546S306000, C546S332000, C514S349000, C514S357000, C514S423000, C514S616000

Reexamination Certificate

active

06803486

ABSTRACT:

BACKGROUND OF THE INVENTION
Nitric oxide (NO) is synthesized enzymatically from arginine in numerous tissues and cell types by a family of enzymes, collectively known as nitric oxide synthase (NOS, E.C. 1.14.13.39). Three principal isoforms of this enzyme have been isolated and characterized, each associated with different physiological functions: the immune response (inducible NOS or iNOS), smooth muscle relaxation (endothelial NOS or eNOS), and neuronal signaling (neuronal NOS or nNOS). All of these isoforms utilize NADPH, FAD, FMN, (6R)-5,6,7,8-tetrahydrobiopterin and heme as cofactors.
Overproduction of NO has been a factor in numerous disease states. NO overproduction by nNOS has been implicated in strokes, migraine headaches, Alzheimer's disease, and with tolerance to and dependence on morphine. iNOS-medicated overproduction of NO has been associated with development of colitis, tissue damage and inflammation, and rheumatoid arthritis.
Animal studies and early clinical trials suggest that NOS inhibitors could be therapeutic in many of these disorders; however, because of the importance of nitric oxide to physiological functioning, potent as well as isoform-selective inhibitors are essential. nNOS inhibition has been targeted for treatment of strokes, and iNOS inhibition for the treatment of septic shock and arthritis. Although there may be pathologies associated with overactivity of eNOS, blood pressure homeostasis is so critical that most investigators believe that therapeutically useful NOS inhibitors should not inhibit eNOS.
Excellent inhibitory potency and selectivity for nNOS over eNOS and iNOS have been achieved with certain prior art (
FIG. 1
) nitroarginine dipeptide amides that have an amine-containing side chain (1-3). See Huang, H.; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. N
&ohgr;
-Nitroarginine-Containing Dipeptide Amides. Potent and Highly Selective Inhibitors of Neuronal Nitric Oxide Synthase.
J. Med Chem
. 1999, 42, 3147-53.
The most potent nNOS inhibitor among these compounds is L-Arg
NO2
-L-Dbu-NH
2
(1) (K
i
=130 nM), which also shows excellent selectivity over eNOS (>1500-fold) and 192-fold selectivity over iNOS. Further, peptidomimetic modifications are, however, invariably necessary before such compounds can be therapeutically useful. Generally, peptides have poor bioavailability and are generally unsuccessful drug candidates.
The foregoing background information, together with other aspects of the prior art, is described more fully and better understood in light of the following publications: (1) Kerwin, J. F., Jr.; Lancaster, J. R., Jr. Nitric Oxide; A New Paradigm for Second Messengers.
Med. Res. Rev
. 1994, 14, 23-74; (2) Kerwin, J. F., Jr.; Heller, M. The Arginine-Nitric Oxide Pathway: A Target for New Drugs.
J. Med. Chem
. 1995, 38, 4342-62; (3) Stuehr, D. J.; Griffith, O. W. Mammalian Nitric Oxide Synthases.
Adv. Enzymol. Relat. Areas Mol. Biol
. 1992, 65, 287-346; (4) MacMicking, J.; Xie, Q. W.; Nathan, C. Nitric Oxide and Macrophage Function.
Annu. Rev. Immunol
. 1997, 15, 323-50; (5) Forstermann, U.; Pollock, J. S.; Schmidt, H. H. H. W.; Heller, M.; Murad, F. Calmodulin-Dependent Endothelium-Derived Relaxing Factor/Nitric Oxide Synthase Activity is Present in the Particulate and Cytosolic Fractions of Bovine Aortic Endothelial Cells.
Prot Natl. Acad. Sci. U.S.A.
1991, 88, 1788-92; (6) Schmidt, H. H. H. W.; Walter, U. NO at Work.
Cell
1994, 78, 919-25; (7)(a) Choi, D. W.; Rothman, S. M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death.
Annu. Rev. Neurosci
. 1990, 13, 171-82; (b) Garthwaite, J.
In the NMDA Receptor
; Watkins, J. C. Collingridge, G. L., Eds.; Oxford University Press.; Oxford, England, 1989; pp 187-205; (8) Thomson, L. L.; Iversen, H. K.; Lassen, L. H.; Olesen, J. The role of nitric oxide in the migrane pain.
CNS Drugs
1994, 2, 417-22; (9) Dorheim, M. A.; Tracey, W. R.; Pollock, J. S.; Grammas, P. Nitric Oxide synthase activity is elevated in brain microvessels in Alzheimer's disease.
Biochem. Biophys. Res. Commun
. 1994, 205, 659-65; (10) Bhargava, H. N. Attenuation of tolerance to, and physical dependence on, morphine in the rat by inhibition of nitric oxide synthase.
Gen. Pharmacol
. 1995, 26, 1049-53; (11) Seo, H. G.; Takata, I.; Nakamura, M.; Tatsumi, H.; Suzuki, K.; Fujii, J.; Taniguchi, N. Introduction of nitric oxide and concommittant suppression of superoxide dismutase in experimental colitis in rats.
Arch. Biochem. Biophys
. 1995, 324, 41-7; (12) Kubes, P.; Suzuki, M.; Granger, D. N. Nitric Oxide; an endogeneous modulator of leukocyte adhesion.
Proc. Natl. Acad. Sci. U.S.A
. 1991, 88, 4651-5; (13) Maclintyre, I.; Zaidi, M.; Towhidul Alam, A. S. M.; Datta, H. K.; Moonga, B. S.; Lidbury, P. S.; Hecker, M.; Vane, J. R. Osteoclastic inhibition; an action of nitric oxide not mediated by cyclic GMP.
Proc. Natl. Acad. Sci. U.S.A
. 1991, 88, 2936-40; (14) Kilbourn, R. G.; Jubran, A.; Gross, S. S.; Griffith, O. W.; Levi, R.; Adams, J.; Lodato, R. F. Reversal of endotoxin-mediated shock by N
G
-methyl-L-arginine, an inhibitor of nitric oxide synthesis.
Biochem. Biophys. Res. Commun
. 1990, 172, 1132-8; (15)(a) Collins, J. L.; Shearer, B. G.; Oplinger, J. A.; Lee, S.; Garvey, E. P.; Salter, M.; Duffy, C.; Burnette, T. C.; Furfine, E. S. N-Phenylamidines as selective inhibitors of human neuronal nitric oxide synthase. Structure-activity studies and demonstration of in vivo activity.
J. Med. Chem
. 1998, 41. 2858-71; (16) Wright, C. W.; Rees, D. D.; Moncada, S. Protective and Pathological roles of nitric oxide in endotoxin shock.
Cardiovasc. Res
. 1992, 26, 48-57; (17) Garvey, E. P.; Oplinger, J. A.; Furfine, E. S.; Kiff, R. J.; Laszlo, F.; Whittle, B. J. R.; Knowles, R. G. 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric oxide synthase in vitro and in vivo.
J. Biol. Chem
. 1997, 272, 4959-63; (18) Huang, H; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. N
&ohgr;
-Nitroarginine-Containing Dipeptide Amides. Potent and Highly Selective Inhibitors of Neuronal Nitric Oxide Synthase.
J. Med Chem
. 1999, 42, 3147-53.


REFERENCES:
patent: 6127420 (2000-10-01), Griffith et al.
patent: 6210875 (2001-04-01), Patterson et al.
patent: 6274557 (2001-08-01), Silverman et al.
Huang, et al., N&ohgr;-Nitroarginine-Containing Dipeptide Amides, Potent and Highly Selective Inhibitors of Neuronal Nitric Oxide Synthase, Journal of Medical Chemistry, vol. 42, 1999, pp. 3147-3153, American Chemical Society, 1999.
Palmer, R.M.J.; Ferrige, A.G.; Moncada, S.; “Nitric oxide release accounts for the biological activity endothelium-derived relaxing factor”, Nature, 1987, 327, 524-526.
Seo, H.G.; Takata, I.; Nakamura, M.; Tatsumi, H.; Suzuki, K.; Fujii, J.; Tanguchi, N.; “Induction of Nitric Oxide Synthase and Concomitant Supression of Superoxide Dismutases in Experimental Colitis in Rats”, Arch. Biochem. & Biophys. 1995, 324, 1, 41-47.
Sheta, E.A.; McMillan, K.; Masters, B.S.S.; “Evidence for a Bidomain Structure of Constitutive Cerebellar Nitric Oxide Synthase”, J. Bio. Chem. 1994, 269, 21, 15147-15153.
Shibuki, K.; Okada, D.; “Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum”, Nature, 1991, 349, 326-328.
Silverman, R.B.; Huang,; Marletta, M.A.; Martasek, P.; “Selective Inhibition of Neuronal Nitric Oxide Synthase by Nw-Nitroarginine-and Phenylalanine-Containing Dipeptides and Dipeptide Esters”, J. Med. Chem. 1997, 40, 2813-2817.
Stuehr, D.J.; Griffth, O.W.; “Mammalian Nitric Oxide Synthases”, Adv. In Enzym. 1992, 65, 287-346.
White, K.A.; Marletta, M.A.; “Nitric Oxide Synthase is a Cytochrome P-450 Type Hemoprotein”, Amer. Chem. Soc. 1992, 31, 29, 6627-6631.
Wolff, D.J.; Gribin, B.J.; “Interferon-&ggr;-Inducible Murine Macrophase Nitric Oxide Synthase: Studies on the Mechanism of Inhibition by Imidazole Agents”, Arch. Biochem. & Biophys. 1994, 311, 2, 293-299.
Wolff, D.J.; Gribin, B.J.; “The Inhibition of the Constitutive and Inducible Nitric Oxide Synthase Isoforms by Indazo

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