Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-09-30
1993-02-09
Siegel, Alan
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514445, 514447, 549 65, 549 68, 549 76, 549 77, A61K 3138, A61K33332, A61K33322
Patent
active
051853639
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to compounds having pharmacological utility, to pharmaceutical compositions comprising the compounds, and to medical methods of treatment. More particularly, this invention concerns compounds which inhibit lipoxygenase enzymes, to methods and compositions for inhibiting lipoxygenase enzymes in human and other mammalian hosts in need of such treatment.
BACKGROUND OF THE INVENTION
5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes (Samuelsson, B., Science, 120: 568 (1983); Hammarstrom, S., Annual Review of Biochemistry, 52: 355 (1983)). This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids with cis,cis-1,4-pentadiene structures, converting them to 1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonic acid, the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli. The initial product of 5-lipoxygenase action on arachidonate is 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which can be reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) or converted to leukotriene A4 (LTA.sub.4). This reactive leukotriene intermediate is enzymatically hydrated to LTB.sub. 4 or conjugated to the tripeptide glutathione to produce LTC.sub.4. LTA.sub.4 can also be hydrolyzed nonenzymatically to form two isomers of LTB.sub.4. Successive proteolytic cleavage steps convert LTC.sub.4 to LTD.sub.4 and LTE.sub.4.
Other products resulting from further oxygenation steps have also been described (Serhan, C. N., Hamberg, M., and Samuelsson, B., Proceedings of the National Academy of Sciences, USA, 81: 5335 (1985); Hansson, G., Lindgren, J. A., Dahlen, S. E., Hedqvist, P., and Samuelsson, B. FEBS Letters, 130: 107 (1984)).
Products of the 5-lipoxygenase cascade are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. (Sirois, P., Advances in Lipid Research, R. Paoletti, D. Kritchevesky, editors, Academic Press, 21: 79 (1985).
The remarkable potencies and diversity of actions of products of the 5-lipoxygenase pathway have led to the suggestion that they play important roles in a variety of diseases. Alterations in leukotriene metabolism have been demonstrated in a number of disease states. Examples of some of these are briefly discussed as follows:
1. Asthma
Slow reacting substance of anaphylaxis (SRS-A) has long been recognized as a potentially important mediator of asthma and other allergic diseases (Orange, R. P. and Austen, K. F., Advances in Immunology, 10: 105, 1969). Upon specific antigen challenge, tissues from allergic animals and humans generate and release SRS-A (Kellaway, C. H. and Trethewie, E. R., Quarterly Journal of Experimental Physiology, 30: 121, 1940; Orange, R. P., Stechschulte, D. J., and Austen, K. F., Journal of Immunology, 105: 1087, 1979; Lewis, R. A., Wasserman, S. I., Goetzl, E. J., and Austen, K. F., Journal of Experimental Medicine, 140: 1133, 1974). It produces a slow and sustained contraction of airway smooth muscle preparations from a variety of species in vitro, including man (Drazen, J. M., Lewis, R. A., Wasserman, S. I., Orange, R. P., and Austen, K. F., Journal of Clinical Investigation, 63: 1, 1979; Piper, P. J., Tippins, J. R., Morris, H. R., and Taylor, G. W., Advances in Prostaglandin and Thromboxane Research, 6: 121, 1980; Brocklehurst, W. E. Progress in Allergy, 6: 539, 1962; Berry, P. A. and Collier, H. O. J., British Journal of Pharmacology, 23: 201, 1964). Intravenous administration of SRS-A to guinea pigs result
Brooks Dee W.
Kerkman Daniel J.
Martin Jonathan G.
Stewart Andrew O.
Summers James B.
Abbott Laboratories
Janssen Jerry F.
Siegel Alan
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