Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1998-02-11
1999-07-06
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514316, 514460, 536 41, 536 182, 546187, 549415, A61K 3135, A61K 3170, C07D30910, C07H 1500
Patent
active
059197684
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to compounds that inhibit the binding of E-selectin, P-selectin or L-selectin to sialyl-Lewis.sup.x and sialyl-Lewis.sup.a and to methods of inhibiting the binding of E-selectin, P-selectin or L-selectin to sialyl-Lewis.sup.x or sialyl-Lewis.sup.a using said compounds. This invention also relates to pharmaceutically active compositions comprising compounds that inhibit the binding of E, P or L-selectin to sialyl-Lewis.sup.x or sialyl-Lewis.sup.a.
BACKGROUND OF THE INVENTION
E-selectin, which has also been called ELAM-1 for endothelial leukocyte adhesion molecule-1 and LECAM-2 for lectin cell adhesion molecule, is a glycoprotein that is found on the surface of endothelial cells, the cells that line the interior wall of capillaries. E-selectin recognizes and binds to the carbohydrate sialyl-Lewis.sup.x (sLe.sup.x), which is present on the surface of certain white blood cells. E-selectin helps white blood cells recognize and adhere to the capillary wall in areas where the tissue surrounding the capillary has been infected or damaged. E-selectin is actually one of three selectins now known. The other two are L-selectin and P-selectin. P-selectin is expressed on inflamed endothelium and platelets, and has much structural similarity to E-selectin and can also recognize sialyl-Lewis.sup.X. L-selectin is expressed on leukocytes and also has much structure similarity to P- and E-selectins. The structure of sialyl-Lewis.sup.X and sialyl-Lewis.sup.a (sLe.sup.a) are shown in formulas I.sub.a and I.sub.b below: ##STR1##
When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream. However, when a tissue is infected or becomes damaged, the white blood cells must be able to recognize the invaded or damaged tissue and be able to bind to the wall of the capillary near the affected tissue and diffuse through the capillary into the affected tissue. E-selectin helps two particular types of white blood cells recognize the affected sites and bind to the capillary wall so that these white blood cells may diffuse into the affected tissue.
There are three main types of white blood cells: granulocytes, monocytes and lymphocytes. Of these categories, E-selectin recognizes sLe.sup.x presented as a glycoprotein or glycolipid on the surface of monocytes and neutrophils. Neutrophils are a subclass of granulocytes that phagocytose and destroy small organisms, especially bacteria. Monocytes, after leaving the bloodstream through the wall of a capillary, mature into macrophages that phagocytose and digest invading microorganisms, foreign bodies and senescent cells.
Monocytes and neutrophils are able to recognize the site where tissue has been damaged by binding to E-selectin, which is produced on the surface of the endothelial cells lining capillaries when the tissue surrounding a capillary has been infected or damaged. Typically, the production of E-selectin and P-selectin is increased when the tissue adjacent to a capillary is affected. P-selectin is present constitutively in storage granules from which it can be rapidly mobilized to the cell surface after the endothelium has been activated. In contrast, E-selectin requires de novo RNA and protein synthesis, and peak expression is reached about 4-6 hours after activation, and declines to basal levels after about 24-48 hours. White blood cells recognize affected areas because sLe.sup.x moieties present on the surface of the white blood cells bind to E-selectin and P-selectin. This binding slows the velocity of white blood cells circulating through the bloodstream, since it mediates the rolling of leukocytes along the activated endothelium prior to integrin-mediated attachment and migration, and helps to localize white blood cells in areas of injury or infection.
While white bloo
REFERENCES:
patent: 5444050 (1995-08-01), Kogan et al.
patent: 5498775 (1996-03-01), Novak et al.
Bui Huong
Dupre Brian
Kassir Jamal M.
Keller Karin M.
Kogan Timothy P.
Lambkin Deborah C.
Texas Biotechnology Corporation
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