Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-03-12
1997-12-30
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
53612313, 536 172, 514 25, A61K 31715, C07H 1500
Patent
active
057030596
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. national stage entry under 35 U.S.C. .sctn. 371 of PCT/GB94/00088, filed Jan. 19, 1994.
FIELD OF THE INVENTION
This invention relates to a series of carbohydrate-based compounds which are useful as anti-inflammatory agents and as agents for the control of tumour metastasis, to the use of such compounds for those purposes, to methods for their preparation, and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
The compounds of the invention are ligands of E-selectin (Endothelial Leucocyte Adhesion Molecule 1), P-selectin (GMP-140) and the L-selectin, which play a crucial role in mediating the adhesion of circulating neutrophils, memory T-cells and certain tumour cell types to cytokine-stimulated endothelial cells. This adhesion is the primary event in the processes of inflammation and metastasis in which neutrophils and tumour cells leave the circulation and infiltrate the tissue. Selectin blockade may provide a therapy for inflammatory states where injury results from an excessive accumulation of neutrophils in the tissue. In this manner, the compounds of the invention may prove beneficial in the treatment of Adult Respiratory Distress Syndrome (ARDS), asthma, reperfusion injury following myocardial infarction, stroke, transplant rejection, inflammatory bowel disease, rheumatoid arthritis and endotoxic and haemmorhagic shock. They may be of therapeutic value in the treatment of chronic skin inflammations such as psoriasis, lichen planus and non-specific contact dermatitis in which high levels of skin-homing memory T cells are implicated. Blockade of E-selectin may also reduce the metastatic potential of tumour types which carry the natural ligands for E-selectin, namely the sialyl Lewis x and sialyl Lewis a antigens.
Evidence for the role of neutrophils in the development of ARDS has been reviewed (S. C. Donnely et al, Thorax, 1992, 47, 260). Neutrophil depletion in a sheep lung model has been shown to reduce microvascular damage (A. C. Heflin, J. Clin. Invest., 1981, 68, 1253). Neutrophil influx associated with late phase response in asthmatic attacks follows a similar time course to the expression of E-selectin by bronchial tissue. In monkeys, anti E-selectin antibody inhibited neutrophil influx and decreased airway obstruction (R. H. Gundel, J. Clin. Invest., 1991, 88, 1407). Neutrophil infiltration is a key factor in reperfusion injury following local ischaemia (W. J. Dreyer et al, Circulation, 1991, 84, 400), and there are many reports of the beneficial effects of blockade (see for example M. J. Horgan, Am. J. Physiol, 1990, 259, P L 315). Inadequate tissue perfusion is also found in haemorrhagic and septic shock (reviewed by N. B. Vedder et al, Prog. Clin. Biol. Res., 1989, 299, 181), where neutrophil infiltration leads to organ damage and failure. In the baboon, septic shock was associated with high expression of the E-selectin in the lung, liver and kidneys (H. Redl, Am. J. Path., 1991, 139, 461).
Inflamed colon or small intestine in Crohn's disease and ulcerative colitis are characterised by high expression of E-selectin and corresponding infux of neutrophils and lymphocytes (M. Koizumi et al, 1992, 103, 840). There is evidence for the chronic expression of E-selectin on the vessels within rheumatoid synovium (A. E. Koch, Lab. Invest., 1991, 64, 313). Lymphocytes isolated from rheumatoid synovium show an enhanced capacity to bind to the E-selectin compared with those from peripheral blood (A. A. Postigo et al, J. Clin. Invest., 1992, 89, 1445). In chronic skin inflammations such as psoriasis, lichen planus and non-specific contact dermatitis, high levels of skin-homing memory T cells are believed to be recruited by expression of E-selectin by inflamed tissue. (L. J. Picker et al, Nature, 1991, 349, 796).
The adhesion event that occurs between circulating neutrophils and endothelial cells in response to an inflammatory stimulus is mediated by binding of leucocyte integrins toextra cellular matrix and adhesion molecules of the Ig superfamily, and by ca
REFERENCES:
Lasky Science Nov. 6, 1992, 258, 964-969.
Hindsgaul, et al., Canadian Journal of Chemistry, vol. 63:2653-2658 (1985).
Allanson, et al., Tetrahedron Letters, vol. 34, No. 24:3945-3948 (1993).
Allanson Nigel Mark
Davidson Alan Hornsby
British Biotech Pharmaceuticals Ltd.
Fonda Kathleen K.
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