Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-05
2003-02-04
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S204000, C548S205000
Reexamination Certificate
active
06515001
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to therapeutic organic compounds and uses thereof, particularly the treatment of chemokine and chemokine receptor mediated diseases.
BACKGROUND OF THE INVENTION
Inflammatory reactions are generally characterized by dramatic movement of leukocytes and fluids from the bloodstream into the inflamed tissues. Chemotactic factors such as C5a, leukotriene B4 (LTB4), and platelet-activating factor (PAF) are thought to mediate the migration of all types of leukocytes in inflammation. However, pathologically, it has been suggested that the types of infiltrating cell populations will vary depending largely upon the stimuli and the interval from the injury (Chemokines in Disease,
Biology and Clinical Research;
(1999) Edited by Caroline A. Hebèrt; Humana Press, Totowa, N.J.).
Many different names have been applied to Interleukin-eight (IL-8), such as neutrophil attractant/activation protein-one (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF) and T-cell lymphocyte chemotactic factor. IL-8 is understood to be a chemoattractant for neutrophils, basophils and a subset of T-cells. It is thought to be produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1&agr;, IL-1&bgr; or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP (Baggiolini, M. et. al., (1989)
J. Clin. Invest.
84, 1045; Schroder, J. et. al., (1987)
J. Immunol.
139, 3474; ibid, (1990)
J. Immunol.
144, 2223; Strieter et. al., (1989)
Science
243: 1467; ibid, (1989)
Journal of Biological Chemistry
264: 10621; Cassatella et. al., (1992)
Journal of Immunology
148: 3216).
Chemokines are chemotactic cytokines that belongs to a large family of chemoattractant molecules involved in the directed migration of immune cells (Schall, T. The Chemokines.
In The Chemokine Handbook;
Thompson, A., Ed., Academic Press: San Diego, Calif., 1994; pp419-460). The physiological role generally assigned to chemokines in the immune process is to elicit mobilization of immune cells against pathogenic organisms by direct recruitment and activation. Based on their structural similarity, chemokines may be subdivided into four subfamilies, CXC, CC, C and CX
3
C, depending on the position of their first two cysteine residues.
In addition to IL-8, GRO-&agr;, GRO-&bgr;, GRO-&ggr; and NAP-2 also belongs to the chemokine &agr;-family. Like IL-8, these chemokines have also been referred to by different names. For instance, GRO-&agr;, -&bgr;, -&ggr; have been referred to as MGSA-&agr;, -&bgr;, and -&ggr;, respectively (Melanoma Growth Stimulating Activity) (Richmond et. al., (1986)
J. Cell Physiology
129, 375; and Chang et. al., (1992)
J. Immunol.
148, 451). Current understanding is that all of the chemokines of the &agr;-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.
IL-8, GRO-&agr;, GRO-&bgr;, GRO-&ggr; and NAP-2 have been reported to promote the accumulation and activation of neutrophils, and these chemokines have accordingly been implicated in a wide range of acute and chronic inflammatory disorders, including psoriasis and rheumatoid arthritis (Baggiolinni et. al (1992)
FEBS Lett.
307, 97; Miller et. al., (1992)
Crit. Rev. Immunol.
12, 17; Oppenheim et. al., (1991)
Annu. Rev. Immunol.
9, 617; Seitz et. al., (1991)
J. Clin. Invest.
87, 463; Miller et. al., (1992)
Am. Rev. Respir. Dis.
146, 427; Donnely et. al., (1993)
Lancet
341, 6430).
IL-8 has been found to stimulate a number of functions of human neutrophils, including induction of shape change (Thelen, M. et. al., (1988)
FASEB J.
2, 2702-2706), release of lysosomal enzymes (Peveri, P. et. al., (1988)
J. Exp. Med.
167, 1547-1559), generation of superoxide (Thelen, M. et. al., (1988)
FASEB J.
2, 2702-2706), generation of biolipids (Schroder, J. M. (1989)
J. Exp. Med.
170, 847-863), and increased expression of adhesion molecules on neutrophils (Paccaud, J. P. et. al., (1990)
Biochem. Biophys. Res. Comm.
166, 187-192). It has chemotactic activity not only for neutrophils but also basophils (White, M. V. et. al. (1989)
Immunol. Lett.
22, 151-154) and IL-3- or granulocyte-macrophage colony-stimulated factor (GM-CSF)-primed eosinophils (Warringa, R. A. J. et. al., (1991)
Blood
77, 2694-2700). IL-8 also induces chemotaxis against CD4
+
and CD8
+
human peripheral blood T lymphocytes (Larsen, C. G. et. al., (1989)
Science
243, 1464-1466). IL-8 enhances the growth-inhibitory activity of neutrophils to
Candida albicans
(Djeu, J. Y. et. al (1990)
J. Immunol.
144, 2205-2210).
IL-8 is also thought to act on nonleukocytic cells such as melanoma cells and synovial fibroblasts (Unemori, E. N. et. al., (1993)
J. Biol. Chem.
268, 1338-1342) in vitro. IL-8 reportedly enhances viral replication, particularly cytomegalovirus, in human fibroblasts in vitro (Murayama, T. et. al., (1994)
J. Virol
68, 7582-7585). IL-8 may significantly inhibit the antiviral activities of interferon-&agr; (Khabar, A. S. A. et. al., (1996)
Eur. Cytokine Netw.
7, 554). IL-8 may also increase the adhesion of unstimulated human umbilical cord vein endothelial cells (HUVECs) (Gimbrone, M. A. Jr. et. al., (1989)
Science
246, 1601-1603), enhance transendothelial migration (Huber, A. R. et. al., (1991)
Science
254, 99-102) and induce angiogenesis in rat cornea (Koch, A. E. et. al.,
Science
258, 1798-1801).
The production of IL-8 in various human diseases has been extensively studied. Clinically, IL-8 has been identified in skin lesions of psoriasis (Schroder J. M. and Christopher E. (1986)
J. Invest. Dermatol.
87, 53-58). IL-8 has also been detected in synoval fluids in patients with rheumatoid arthritis (Brennan, F. et. al., (1990)
Eur. J. Immunol.
20, 2141-2144), osteoarthritis (Symon, J. A. et al., (1992)
Scand. J. Rheumatol.
21, 92-94; Kaneko, S. et. al., (2000)
Cytokines Cell Mol. Ther.
6(2) 71-79), and gout (Terkeltaub, R. et. al., (1991)
Arthritis Rheum.
34, 894-903), suggesting a pathological role for IL-8 in the establishment of arthritis. Increased IL-8 levels have also been detected in other biological fluids such as bronchoalveolar lavage fluids (BALF), pleural fluids (Carrè, P. et. al., (1991)
J. Clin. Invest.
88, 1802-1810), and urine (Broaddus, V. C. et. al., (1992)
Am. Rev. Repir. Dis.
146, 825-830). Levels of IL-8 in BALF reportedly increase in patients with adult respiratory distress syndrome (ARDS) (miller, E. J. et. al., (1991)
Am. Rev. Repir. Dis.
146, 427-432) and idiopathic pulmonary fibrosis (Carrè, P. et. al., (1991)
J. Clin. Invest.
88, 1802-1810). Elevated serum and bronchoalveolar lavage fluid levels of IL-8 and granulocyte colony-stimulating factor (G-CSF) have been associated with the acute chest syndrome (ACS) in patients with sickle cell disease (Abboud, M. R. et. al., (2000)
Br. J. Haematol.
111 (2) 482-490). Urinary IL-8 level increase in patients with urosepsis (Olszyna, D. P. et. al., (2000)
J. Infect. Dis.
182 (6) 1731-1737), urinary tract infection (UTI), and several types of glomerulonephritis such as Ig A nephropathy, acute glomerulonephritis (AGN), purpura nephritis, membranous proliferative glomerulonephritis (MPGN), and lupus nephritis (Wada, T. et. al., (1994)
Kidney Int.
46, 455-460). These clinical observations have been taken to imply that detection of IL-8 in biofluids from patients may be an important indicator of the acute inflammatory diseases.
Colonization of the gastric mucosa with
Helicobacter pylori
is reportedly associated with a dense infiltration of granulocytes into the lamina propria in the active phase of gastritis. In one study, antral biopsies from 27 patients with
H. pylori
-associated gastritis and 25 from
H. pylori
-negative individuals were analyzed for epithelial cell-derived neutrophil-activating protein 78 (ENA-78) and IL-8 mRNA by semiquantitative reverse transcription (RT)-PCR (Rieder, G. et. al., (2001)
Infect. Immun.
69(1) 81-88).
Cheng Nick
Salari Hassan
Saxena Geeta
Tudan Christopher R.
Bozicevic, Field & Francis
Chemokine Therapeutic Corporation
Field Bret E.
McKane Joseph K.
Saeed Kamal
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