Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-03-20
1998-10-13
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514637, 514357, 514438, 514471, 514633, 514378, A61K 31155, A61K 3144, A61K 3138, A61K 3134
Patent
active
058212671
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to amidino derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
2. Related Art
It has been known since the early 1980's that the vascular relaxation brought about by acetycholine is dependent on the presence of the endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years and NO is the active component of amylnitrite, glyceryltrinitrite and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.
NO is the endogenous stimulator of the soluble guanylate cyclase and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al. Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al. Pharmacological Reviews, 43, 109-142 (1991). It is now thought that excess NO production may be involved in a number of conditions, particularly conditions which involve systemic hypotension such as toxic shock and therapy with certain cytokines.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three types of NO synthase as follows:
(i) a constitutive, Ca.sup.++ /calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca.sup.++ /calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca.sup.++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible NO synthase synthesizes NO for long periods.
The NO released by the constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase.
There is also a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis. Accordingly, further conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis.
Conditions in which there is an advantage in inhibiting NO production from L-arginine include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy. Further conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune diseases and/or inflammatory conditions such as those affecting the joints, for example arthritis or inflammatory bowel disease, cardiovascular ischemia, diabetes, hyperalgesia (allodynia) cerebral ischemia (Both focal ischemia, thrombotic stroke and g
REFERENCES:
patent: 3445517 (1969-05-01), Mills
patent: 3632593 (1972-01-01), Gautier et al.
patent: 4713369 (1987-12-01), Stiiber
patent: 5059712 (1991-10-01), Griffith
patent: 5081148 (1992-01-01), Braquet et al.
patent: 5132453 (1992-07-01), Griffith
patent: 5196450 (1993-03-01), Sjoerdsma et al.
patent: 5273875 (1993-12-01), Griffith
patent: 5281627 (1994-01-01), Griffith
patent: 5350770 (1994-09-01), Elford et al.
patent: 5362744 (1994-11-01), Purchase, Jr. et al.
patent: 5364881 (1994-11-01), Griffith et al.
patent: 5464858 (1995-11-01), Griffith et al.
Gould et al., "Nucleoside Intermediates in Blasticidin S Biosynthesis Identified by the In Vivo Use of Enzyme Inhibitors", Can. J. Chem., vol. 72, pp. 6-11, 1994.
Tsunematsu et al., ".beta.-Naphthylamides of Guanidinophenyl Amino Acids as Substrates of Aminopeptidases", Chem. Pharm. Bull., vol. 36, No. 3, pp. 1205-1209, 1988.
Funabashi et al., "A New Anti-MRSA Dipeptide, TAN-1057 A", Tetrahedron, vol. 49, No. 1, pp. 13-28, 1993.
Prabhakaran et al., "Studies on Nitrogen Metabolism Using .sub.13 C NMR Spectroscopy. 5..sub.1 Metabolism of L-.alpha.-Arginine in the Biosynthesis of Blasticidin S", Tetrahedron, vol. 27, No. 33, pp. 3815-3818, 1986.
Stuehr et al., "Mammalian Nitric Oxide Synthases", Advances in Enzymology, vol. 65, 1992, (p. 317).
Plapp et al., "Determination of .epsilon.-Acetimidyllysine in Proteins" Analytical Biochemistry, vol. 62, pp. 291-294, 1974.
Rees et al., "Characterization of Three Inhibitors of Endothelial Nitric Oxide Synthase in vitro and in vivo", Br. J. Pharmacol., vol. 101, pp. 746-752, 1990.
Proudfoot et al., "Conformation-directed Recombination of Enzyme-activated Peptide Fragments: A Simple and Efficient Means to Protein Engineering", J. Bio. Chem., vol. 264, No. 15, pp. 8764-8770, 1989.
Palacios, et al., "Nitric Oxide from L-Arginine Stimulates the Soluble Guanylate Cyclase in Adrenal Glands", Biochemical and Biophysical Research Communications, vol. 165, No. 2, pp. 802-809, 1989.
Knowles et al., "Kinetic Characteristics of Nitric Oxide synthase from Rat Brain", Biochem. J., vol. 269, pp. 207-210, 1990.
CA 107, 40336y, 1987.
CA 63, 5641d, 1965.
CA 97, 38442m, 1982.
CA 76, 43768t, 1972.
CA 118, 72838g, 1993.
CA 64, 17593h, 1966.
CA 115, 29868t, 1991.
Ca 104, 202858, 1986.
Fok Kam F.
Tjoeng Foe S.
Webber R. Keith
Bennett Dennis
G.D. Searle & Co.
Lambkin Deborah C.
Scrivner Alan L.
LandOfFree
Amidino derivatives useful as nitric oxide synthase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Amidino derivatives useful as nitric oxide synthase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amidino derivatives useful as nitric oxide synthase inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-313588