Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-19
2002-10-22
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254050, C514S319000, C514S326000, C514S400000, C544S139000, C544S370000, C546S205000, C546S210000, C548S300100, C548S314700
Reexamination Certificate
active
06469002
ABSTRACT:
BACKGROUND OF THE INVENTION
Chemokines constitute a family of small cytokines that are produced in inflammation and regulate leukocyte recruitment (Baggiolini, M. et al.,
Adv. Immunol
., 55: 97-179 (1994); Springer, T. A.,
Annu. Rev. Physiol
., 57: 827-872 (1995); and Schall, T. J. and K. B. Bacon,
Curr. Opin. Immunol
., 6: 865-873 (1994)). Chemokines are capable of selectively inducing chemotaxis of the formed elements of the blood (other than red blood cells), including leukocytes such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes, such as T cells and B cells. In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca
2+
]
i
), granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
The chemokines are related in primary structure and share four conserved cysteines, which form disulfide bonds. Based upon this conserved cysteine motif, the family can be divided into distinct branches, including the C—X—C chemokines (&agr;-chemokines) in which the first two conserved cysteines are separated by an intervening residue (e.g., IL-8, IP-10, Mig, I-TAC, PF4, ENA-78, GCP-2, GRO&agr;, GRO&bgr;, GRO&ggr;, NAP-2, NAP-4), and the C—C chemokines (&bgr;-chemokines), in which the first two conserved cysteines are adjacent residues (e.g., MIP-1&agr;, MIP-1&bgr;, RANTES, MCP-1, MCP-2, MCP-3, I-309)(Baggiolini, M. and Dahinden, C. A.,
Immunology Today
, 15:127-133 (1994)). Most CXC-chemokines attract neutrophil leukocytes. For example, the CXC-chemokines interleukin 8 (IL-8), GRO alpha (GRO&agr;), and neutrophil-activating peptide 2 (NAP-2) are potent chemoattractants and activators of neutrophils. The CXC-chemokines designated Mig (monokine induced by gamma interferon) and IP-10 (interferon-gamma inducible 10 kDa protein) are particularly active in inducing chemotaxis of activated peripheral blood lymphocytes. CC-chemokines are generally less selective and can attract a variety of leukocyte cell types, including monocytes, eosinophils, basophils, T lymphocytes and natural killer cells. CC-chemokines such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), and the macrophage inflammatory proteins 1&agr; and 1&bgr; (MIP-1&agr; and MIP-1&bgr;) have been characterized as chemoattractants and activators of monocytes or lymphocytes, but do not appear to be chemoattractants for neutrophils.
Chemokines (e.g., CC- and CXC-chemokines) act through receptors which belong to a superfamily of seven transmembrane spanning G protein-coupled receptors (Murphy, P. M.,
Annu. Rev. Immunol
., 12: 593-633 (1994); Gerard, C. and N. P. Gerard,
Curr. Opin. Immunol
., 6: 140-145 (1994)). This family of G protein-coupled (serpentine) receptors comprises a large group of integral membrane proteins, containing seven transmembrane-spanning regions. The receptors are coupled to G proteins, which are heterotrimeric regulatory proteins capable of binding GTP and mediating signal transduction from coupled receptors, for example, by the production of intracellular mediators.
The chemokine receptors can be divided into groups, which include, CC-chemokine receptors 1 through 9 (CCR1-CCR9), which can bind certain CC-chemokines, and CXC-chemokine receptors 1 through 4 (CXCR1-CXCR4), which can bind certain CXC-chemokines. In general, the CC-chemokine receptors occur on several types of leukocytes, and are important for the migration of monocytes, eosinophils, basophils, and T cells (Qin, S. et al.,
Eur. J. Immunol
., 26: 640-647 (1996); Carr, M. W. et al.,
Proc. Natl. Acad. Sci. USA
, 91(9): 3652-3656 (1994); Taub, D. D. et al.,
J. Clin. Invest
., 95(3): 1370-1376 (1995); Neote, K. et al.,
Cell
, 72: 415-425 (1993); Gao, J.-L. et al.,
J. Exp. Med
., 177: 1421-1427 (1993); Charo, I. F. et al.,
Proc. Natl. Acad. Sci. USA
, 91: 2752-2756 (1994); Myers, S. J. et al.,
J. Biol. Chem
., 270: 5786-5792 (1995); Combadiere, C. et al.,
J. Biol. Chem
., 270(27): 16491-16494 (1995); Ponath, P. D. et al.,
J. Exp. Med
., 183: 2437-2448 (1996); Daugherty, B. L. et al.,
J. Exp. Med
., 183: 2349-2354 (1996); Power, C. A. et al.,
J. Biol. Chem
., 270: 19495-19500 (1995); Hoogewerf, A. J. et al.,
Biochem. Biophys. Res. Commun
., 218: 337-343 (1996); and Samson, M. et al.,
Biochemistry
, 35: 3362-3367 (1996)).
In contrast, the two IL-8 receptors, CXCR1 and CXCR2, are largely restricted to neutrophils and are important for the migration of neutrophils (Baggiolini, M. et al.,
Adv. Immunol
., 55: 97-179 (1994)). The IL-8 receptors, CXCR1 (IL-8R1, interleukin-8 receptor type 1; Holmes, W. E. et al.,
Science
, 253: 1278-1280 (1991)) and CXCR2 (IL-8R2, interleukin-8 receptor type 2; Murphy, P. M. and H. L. Tiffany,
Science
, 253: 1280-1283 (1991)) both bind IL-8 and appear to recognize the NH
2
-terminal Glu-Leu-Arg (ELR) motif as an essential binding epitope observed in CXC-chemokines that induce neutrophil chemotaxis (Clark-Lewis, I. et al.,
J. Biol. Chem
., 266: 23128-23134 (1991); Hebert, C. A. et al.
J. Biol. Chem
., 266: 18989-18994 (1991); and Clark-Lewis, I. et al.,
Proc. Natl. Acad. Sci. USA
, 90: 3574-3577 (1993)). The CXCR1 receptor of human neutrophils binds only IL-8 with high affinity, while the CXCR2 receptor binds IL-8 with similar affinity as CXCR1 but also binds other ELR-containing CXC-chemokines (Baggiolini, M. et al.,
Adv. Immunol
., 55: 97-179 (1994)). Both receptors are capable of coupling to the same G protein &agr;-subunits, exhibiting functional coupling to G&agr;i2, G&agr;i3, G&agr;14, G&agr;15, and G&agr;16 (Wu, et al.,
Science
, 261: 101-103 (1993)). Whether these two receptor subtypes play distinct physiologic roles is not clear.
In contrast to granulocytes and monocytes, lymphocyte responses to chemokines are not well understood. Notably, none of the receptors of known specificity appear to be restricted to lymphocytes and the chemokines that recognize these receptors cannot, therefore, account for events such as the selective recruitment of T lymphocytes that is observed in T cell-mediated inflammatory conditions. Moreover, although a number of proteins with significant sequence similarity and similar tissue and leukocyte subpopulation distribution to known chemokine receptors have been identified and cloned, the ligands for these receptors remain undefined. Thus, these proteins are referred to as orphan receptors. The characterization of the ligand(s) of a receptor, is essential to an understanding of the interaction of chemokines with their target cells, the events stimulated by this interaction, including chemotaxis and cellular activation of leukocytes, and the development of therapies based upon modulation of receptor function.
A chemokine receptor that binds the CXC-chemokines IP-10 and Mig has been cloned and characterized (Loetscher, M. et al.,
J. Exp. Med
., 184: 963-969 (1996)). The receptor mediates Ca
2+
(calcium ion) mobilization and chemotaxis in response to IP-10 and Mig. CXCR3 expressing cells show no significant response to the CXC-chemokines IL-8, GRO&agr;, NAP-2, GCP-2 (granulocyte chemotactic protein-2), ENA78 (epithelial-derived neutrophil-activating peptide 78), PF4 (platelet factor 4), or the CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1&agr;, MIP-1&bgr;, RANTES, I309, eotaxin or lymphotactin. Moreover, a third ligand for CXCR3, I-TAC (Interferon-inducible T cell Alpha Chemoattractant), has also been found to bind to the receptor with high affinity and mediate functional responses (Cole, K. E. et al.,
J. Exp. Med
., 187: 2009-2021 (1998)).
The restricted expression of human CXCR3 in activated
Komatsu Rie
Kotera Osamu
LaRosa Gregory J.
Luly Jay R.
Ohshima Etsuo
Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmaceuticals Inc.
Stockton Laura L.
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