Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-04
2003-05-13
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S518000
Reexamination Certificate
active
06562859
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to inhibition of inflammation by administration of a pharmacologically active ureido derivative of poly-4-amino-2-carboxy-1-methyl pyrrole.
BACKGROUND OF THE INVENTION
Inflammatory reactions are serious medical indications arising from a variety of conditions. Essential to the early inflammatory response is the selective recruitment of leukocytes into the affected tissue(s). This process is controlled, in part, by chemokines, which are small (8-10 kD), inducible cytokines that act primarily as chemoattractants and activators of specific types of leukocytes in a variety of immune and inflammatory responses (Oppenheim et al.,
Ann. Rev. Immunol
., 9, 617-648 (1991); and Taub et al.,
Cytokine
, 5, 175-179 (1993)). Chemokines are produced in response to an array of factors, including viruses, bacterial products, IL-1, TNF, C5a, LTB4, and IFNs (Strieter et al.,
J. Immunol
. 156, 3583-3586 (1996)). Chemokines have been detected during inflammation in the skin, brain, joints, meninges, lungs, blood vessels, kidneys, and gastrointestinal tract. Within these organs, chemokines have been identified in many types of cells, indicating that most cells secrete chemokines given the appropriate stimulus.
Chemokines have been subdivided into families based on the arrangement of the conserved cysteine residues of the mature proteins (Baggiolini et al.,
Adv. Immunol
., 55, 97-179 (1994); and Baggiolini et al.,
Ann. Rev. Immunol
., 15, 675-705 (1997). The &agr;- and &bgr;-chemokines, which contain four conserved cysteines, belong to the largest families. The CXC or &agr;-chemokines are those which have one amino acid residue separating the first two conserved cysteine residues, whereas the CC or &bgr;-chemokines are those in which the first two conserved cysteine residues are adjacent. Additionally, there are at least two other families, including the C or &ggr;-chemokines, which lack two (the first and third) of the four cysteine residues (Kelner et al.,
Science
, 266, 1395-1359 (1994)), and the CXXXC chemokines, in which the first two cysteine residues are separated by three amino acids (Bazan et al.
Nature
, 385, 640-644 (1997)).
Within the CXC or &agr;-chemokine family, there are chemokines that contain a characteristic glutamic acid-leucine-arginine (ELR) sequence immediately preceding the first cysteine residue near the N terminus and those that lack this sequence (Clark-Lewis et al.,
J. Biol. Chem
., 266, 23128-23134 (1991)). CXC chemokines possessing the ELR sequence (e.g., human IL-8, mouse KC, mouse MIP-2, mouse LIV, ENA-78, GCP-2, and GRO&agr;, &bgr; and &ggr;) are chemoattractants and activators of neutrophils, whereas CXC chemokines lacking the sequence (e.g., IP10/mouse CRG, PBSF/SDF-1, and PF4) act primarily on lymphocyte populations. The CC or &bgr;-chemokines (e.g., MIP-1&agr;, MIP-1&bgr;, HCC-1, LEC, TARC, Eotaxin and RANTES) and the C or &ggr;-chemokines (e.g., Lymphotactin) chemoattract and activate monocytes, lymphocytes, dendritic cells, eosinophils, and basophils with variable selectivity.
Chemokines mediate their chemotactic and other activities by binding to specific G-protein-coupled cell-surface receptors on target cells (Premack et al.,
Nat. Med
., 2, 1174-1178 (1996); and Murphy et al.,
Ann. Rev. Immunol
, 12, 593-633 (1994)). Like other G-protein-coupled receptors, chemokine receptors are functionally linked to phospholipases through G proteins and receptor activation leads to, among other things, the generation of inositol triphosphate, the release of intracellular calcium, and the activation of protein kinase C (Lodi et al.,
Science
, 263, 1762-1767 (1994)). To date, five human CXC chemokine receptors (CXCR1 through CXCR5), eight human CC chemokine receptors (CCR1 through CCR8), and one human CXXXC chemokine receptor (CX
3
CR1) have been identified. While some receptors are restricted to certain cell types, others are widely expressed on a variety of cells. Further, chemokine receptors may be constitutively expressed on some cells and inducible on others, and may also be sensitive to the state of cell activation and differentiation. Finally, some chemokine receptors are also expressed on nonhematopoietic cells, including neurons, astrocytes, epithelial cells, and endothelial cells, suggesting further roles for the chemokine system.
Additionally, recent work has shown that some viral genomes are capable of encoding chemokine and chemokine receptor homologues (Gao et al.,
J. Biol. Chem
., 269, 28539-28542 (1994); and Ahuja et al.,
J. Biol. Chem
., 268, 20691-20694 (1993)). For example, the open reading frame (ORF) US28 of the human Cytomegalovirus (CMV) encodes a protein that shares approximately 30% sequence homology with the CC chemokine receptor CCR-1 and is capable of binding the MIP-1&agr;, MIP-1&bgr;, MCP-1 and RANTES chemokines in vitro. Similarly, the ORF ECRF3 of
Herpes saimiri
encodes a protein that is 30% homologous with the IL-8 chemokine receptors and able to bind IL-8, GRO-&agr;, GRO-&bgr; and NAP-2 chemokines. Other human herpesviruses (HHV) also have been shown to express chemokine-receptor homologues that can bind human chemokines (Luster,
New Engl. J. Med
., 338, 436-445 (1998); Soldan et al.,
Nature Med
., 3, 1394-1397 (1997); and Wells et al.,
TIPS
, 19, 376-379 (1998)). For example, Kaposi's sarcoma-associated HHV8 expresses receptor homologues that cause the infected cell to respond to CXC chemokines, such as IL-8, SDF-1&agr; and IP10. The HHV6 virus, which has been found in nervous system tissue characterized by the active myelin destruction associated with multiple sclerosis (Soldan (1997), supra), encodes a &bgr;-chemokine receptor that is capable of binding MIP-1&agr;, MIP-1&bgr;, RANTES, and MCP-1 chemokines (Isegawa et al.,
J. Vir
., 72, 6104-6112 (1998)). Significantly, in contrast to other viruses, such as the HIV-1 virus, which infects its host's cells via the host's chemokine receptors, the herpesviruses enter their host's cells via the Pol receptor. Once the herpesvirus gains entry into the cell, it produces virally encoded chemokines and chemokine receptors, which are effectively masked from the host cell's immune system.
The secretion of chemokines has been detected in a wide variety of diseases characterized by inflammatory reactions resulting from the selective accumulation and activation of leukocytes in the affected tissue(s) (see Strieter (1996), supra). The type of inflammatory infiltrate that characterizes a specific disease is controlled, in part, by the type of chemokines expressed in the diseased tissue. For example, patients with acute respiratory distress syndrome, which is characterized by a massive influx of neutrophils into the tissue, exhibit an elevated concentration of potent neutrophil chemoattractants. Recently, it has been shown that IL-8 production is also increased in reperfusion injury, which similarly involves the recruitment and activation of neutrophils (Strieter (1996), supra; and Karakurum et al.,
J. Clin. Invest
., 93, 1564-1570 (1994)). Patients suffering from asthma demonstrate a selective accumulation and activation of eosinophils in lung tissue, correlating with an elevated level of Eotaxin, RANTES, and MIP-1&agr;. Similarly, monocyte chemoattractant proteins play an important role in allergic inflammation, which is also characterized by the activation and migration of eosinophils into the affected tissue(s). Other disease states associated with inflammatory responses mediated through chemokines include arthritis, non-bacteria-mediated respiratory distress syndrome, and blunt force trauma, as well as the demyelination of nerve cells associated with multiple sclerosis.
Those skilled in the art will appreciate that prior art methods of alleviating or mitigating the negative effects of inflammation are limited. This presents a serious problem for those patients who can not tolerate current available medications, such as aspirin, which is used to treat blunt force trauma, or anti-inflammatory agen
Howard O. M. Zack
Murphy William J.
Oppenheim Joost J.
Sausville Edward A.
Jones Dwayne C.
Leydig , Voit & Mayer, Ltd.
The United States of America as represented by the Department of
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