Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-20
2004-03-16
Solola, Taofiq A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S210010, C514S426000, C544S107000, C548S557000, C564S139000
Reexamination Certificate
active
06706712
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases, allergic and autoimmune diseases, and in particular, asthma, rheumatoid arthritis, atherosclerosis, and multiple sclerosis.
BACKGROUND OF THE INVENTION
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Luster,
New Eng. J. Med
. 1998, 338, 436-445 and Rollins,
Blood
1997, 90, 909-928). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1&agr;, MIP-1&bgr;, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (−1 and −2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in: Horuk,
Trends Pharm. Sci
. 1994, 15, 159-165) which are termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1&agr;, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al.,
Cell
1993, 72, 415-425, and Luster,
New Eng. J. Med
. 1998, 338, 436-445); CCR-2A and CCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo, et al.,
Proc. Natl. Acad. Sci. USA
1994, 91, 2752-2756, and Luster,
New Eng. J. Med
. 1998, 338, 436-445); CCR-3 (or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al.,
J. Biol. Chem
. 1995, 270, 16491-16494, and Luster,
New Eng. J. Med
. 1998, 338, 436-445); CCR-4 (or “CKR-4” or “CC-CKR-4”) [TARC, MIP-1&agr;, RANTES, MCP-1] (Power, et al.,
J. Biol. Chem
. 1995, 270, 19495-19500, and Luster,
New Eng. J. Med
. 1998, 338, 436-445); CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1&agr;, RANTES, MIP-1&bgr;] (Sanson, et al.,
Biochemistry
1996, 35, 3362-3367); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba, et al.,
J. Biol. Chem
. 1997, 272, 14893-14898); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al.,
J. Leukoc. Biol
. 1997, 62, 634-644); CCR-8 (or “CKR-8” or “CC-CKR-8”) [I-309, TARC, MIP-1&bgr;] (Napolitano et al.,
J. Immunol
., 1996, 157, 2759-2763, and Bernardini, et al.,
Eur. J. Immunol
. 1998, 28, 582-588); CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini, et al.,
DNA and Cell Biol
. 1997, 16, 1249-1256); and CCR-11 [MCP-1, MCP-2, and MCP-4] (Schweickert, et al.,
J. Biol. Chem
. 2000, 275, 90550).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed in: Wells and Schwartz,
Curr. Opin. Biotech
. 1997, 8, 741-748). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
The chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis (reviewed in: Bharat K. Trivedi, et al,
Ann. Reports Med. Chem
. 2000, 35, 191; John Saunders and Christine M. Tarby,
Drug Disc. Today
1999, 4, 80; Brett A. Premack and Thomas J. Schall,
Nature Medicine
1996, 2, 1174). For example, the chemokine monocyte chemoattractant-1 (MCP-1) and its receptor CC Chemokine Receptor 2 (CCR-2) play a pivotal role in attracting leukocytes to sites of inflammation and in subsequently activating these cells. When the chemokine MCP-1 binds to CCR-2, it induces a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of leukocyte migration. Demonstration of the importance of the MCP-1/CCR-2 interaction has been provided by experiments with genetically modified mice. MCP-1 −/− mice had normal numbers of leukocytes and macrophages, but were unable to recruit monocytes into sites of inflammation after several different types of immune challenge (Bao Lu, et al.,
J. Exp. Med
. 1998, 187, 601). Likewise, CCR-2 −/− mice were unable to recruit monocytes or produce interferon-&ggr; when challenged with various exogenous agents; moreover, the leukocytes of CCR-2 null mice did not migrate in response to MCP-1 (Landin Boring, et al.,
J. Clin. Invest
. 1997, 100, 2552), thereby demonstrating the specificity of the MCP-1/CCR-2 interaction. Two other groups have independently reported equivalent results with different strains of CCR-2 −/− mice (William A. Kuziel, et al.,
Proc. Natl. Acad. Sci. USA
1997, 94, 12053, and Takao Kurihara, et al.,
J. Exp. Med
. 1997, 186, 1757). The viability and generally normal health of the MCP-1 −/− and CCR-2 −/− animals is noteworthy, in that disruption of the MCP-1/CCR-2 interaction does not induce physiological crisis. Taken together, these data lead one to the conclusion that molecules that block the actions of MCP-1 would be useful in treating a number of inflammatory and autoimmune disorders. This hypothesis has now been validated in a number of different animal disease models, as described below.
Several studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating rheumatoid arthritis. A DNA vaccine encoding MCP-1 was shown recently to ameliorate chronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al.,
J. Clin. Invest
. 2000, 106, 361). Likewise, inflammatory disease symptoms could be controlled via direct administration of antibodies for MCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al.,
J. Pathol
. 1997, 182, 106), or streptococcal cell wall-induced arthritis (Ralph C. Schimmer, et al.,
J. Immunol
. 1998, 160, 1466). Perhaps most significantly, a peptide antagonist of MCP-1, MCP-1(9-76), was shown both to prevent disease onset and to reduce disease symptoms (depending on the time of administration) in the MRL-lpr mouse model of arthritis (Jiang-Hong Gong, et al.,
J. Exp. Med
. 1997, 186, 131).
Three key studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in
Bristol-Myers Squibb Pharma Company
Solola Taofiq A.
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