Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
2001-01-22
2004-03-16
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
Reexamination Certificate
active
06706767
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to small molecule therapeutics, particularly tricyclic compounds such as phenanthrene diones.
BACKGROUND OF THE INVENTION
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 of chemokines in the immune process is to elicit mobilization of immune cells against pathogenic organisms by direct recruitment and activation.
Chemokines are small proteins that are divided into two main classes, based on the position of the first two cysteines, the C—X—C and C—C families of chemokines (two smaller branches of this family have been described, the C and CX
3
C subfamilies). Chemokines and their receptors have been implicated as having important roles in a number of disease states, including Guillian-Barre Syndrome (GBS), Rheumatoid arthritis (RA), Allograft rejection, Psoriasis, Atherosclerosis, Asthma, Angiogenesis, Inflammatory Bowel Disease (IBD), Acute Respiratory Distress Syndrome (ARDS), and all other diseases known as autoimmune diseases.
In addition to their well-established role in the immune systems, recent studies strongly suggesting their involvement in the maintenance of Central Nervous System (CNS) homeostasis, in neuronal patterning during ontogeny and as potential mediators of neuroinflammation, playing an essential role in leukocyte infiltration into the brain (Mennicken, F. et. al., (1999)
Trends Pharmacol. Sci.
20 (2): 73-78). Their expression is rapidly induced by various neuroinflammatory stimuli, implicating them in various neurological disorders such as trauma, stroke, and Amyotropic Lateral Sclerosis (ALS), Parkinson's, and Alzheimer's disease, in tumor induction and in neuroimmune disease such as multiple sclerosis (MS) or acquired immunodeficiency syndrome (AIDS). Both MS and GBS, are initiated by an autoimmune reaction involving T-lymphocytes (T-cells).
Multiple Sclerosis (MS) is a disease that primarily afflicts young adults. The diseases is often initially characterized by temporary partial paralysis, with remission of disease followed by relapses of greater severity and duration resulting ultimately in permanent disability in many cases. One of the hallmarks of MS disease is the infiltration and activation of peripheral blood leukocytes into the brain. This along with central nervous system immune cell activation may lead to active demyelination of the central nervous system.
Psoriasis, a common genetic skin disease, is a well known angiogenesis-dependent disorder that is characterized by marked dermal neovascularization. Keratinocytes isolated from psoriatic plaques demonstrate a greater production of angiogenic activity, as compared to normal keratinocytes. This aberrant phenotype is due, in part, to a combined defect in the overproduction of the angiogenic cytokine IL-8, and a deficiency in the production of the angiogenesis inhibitor, thrombospondin-1, resulting in a proangiogenic environment (Keane, M. P. and Strieter, R. M. (1999) in Mantovani A (ed):
Chemokines
. Chem Immunol. Basel, Karger, 72: 86-101).
In rheumatoid arthritis (RA), the unrestrained proliferation of fibroblasts and capillary blood vessels leads to the formation of prolonged and persistent granulation tissue of the pannus whose degradative enzymes contribute to profound destruction of joint spaces. In both psoriasis and rheumatoid arthritis, CXC Chemokine specifically IL-8 plays a very important role (Nickoloff, B. J. et. al., (1994)
Am. J. Pathol.
144: 820-828). Finding an antagonist for these specific chemokines or Chemokine receptors can be a novel approach in the treatment of solid tumors, inflammatory diseases and chronic fibroproliferative disorders.
Atherosclerosis is a disease appearing not only at old age but also in early adulthood. Atherosclerosis is a cardiovascular disease related to the accumulation of fatty streak around arteries. These arterial fatty streaks are composed of lipid-laden macrophages (foam cells) and is the precursor of more complex and dangerous lesions. The participation of inflammatory cells in atherosclerosis is a well known process that involves numerous molecules including chemotactic cytokines (chemokines) for their entry into the vessel wall. The CC Chemokine, MCP-1 and its receptor, CCR-2, has been identified as an extremely potent and has been cloned and characterized in some detail (Charo, I. F. (1999) Mantovani A (ed):
Chemokines
, Chem Immunol. Basel, Karger, 72: 30-41). With regard to CCR, the available studies support an important role for MCP-1 in the development of early atherosclerosis lesions and in T-cell polarizations. The role of classic CXC Chemokine, IL-8 (KC/growth-related oncogene alpha in mice) and its receptor CXCR-2 has shown physiological significance in pathogenesis of atherosclerosis. CXCR-2 is strongly expressed on macrophages (Mphi) in atherosclerosis lesion (Boisvert, W. A. et. al., (2000)
Immunol. Res.
21(2-3): 129-137).
During inflammation, neutrophils are removed from inflammatory sites by a process of programmed cell death known as apoptosis, leading to their recognition and phagocytosis by macrophages (Savill, J. S. et. al., (1989)
Journal of Clinical Investigation
83:865). Any significant delay in neutrophil apoptosis can lead to excessive accumulation and damage to surrounding tissues (Hallet, M. B. and Lloyds, D., (1995)
Immunology Today
16: 264). Tumor necrosis factor-alpha (TNF-&agr;) has been shown to induce extensive apoptosis in neutrophils within three hours.
This is the latest field in research to understand the cause of acute inflammatory diseases such as, inflammatory bowel diseases (IBD) and acute respiratory distress syndrome (ARDS). Finding an inhibitor which can inhance apoptosis can lead to disease cure for rheumatoid arthritis, inflammatory bowl disease, lung disease, gouty inflammation, and ARDS etc. Activated neutrophils plays a major role in the pathogenesis of acute respiratory distress syndrome, and persistence of pulmonary neutrophils is related to poor survival. Granulocyte colony stimulating factor (G-CSF) as well as IL-8 plays a role in the mechanisms of pulmonary neutrophilia in acute respiratory distress syndrome (Aggarwal, A. et. al., (2000)
Eur. Respir. J.
15(5): 895-901 and Dunican, A. L. et. al., (2000)
Shock
14(3):248-288, discussion page 288-289) as well as in inflammatory bowl diseases (Brannigan, A. E. et. al., (2000)
Shock
13(5): 361-366).
Monocyte chemoattractant protein-1 (MCP-1) was the first CC Chemokine to be characterized biologically and has been shown to attract monocytes but not neutrophils (Baggiolini M, Dewald B, Moser B. (1994) Interleukin-8 and related chemotactic cytokines —CXC and CC chemokines.
Adv. Immunol.
55:97-179). MCP-1 is a member of the &bgr;-Chemokine family which acts through specific receptors to recruit monocytes, basophils, and T-lymphocytes to sites of inflammation.
MCP-1 has been reported to stimulate an increase in cytosolic free calcium and the respiratory burst in monocytes, and to activate monocyte-mediated tumoristatic activity, as well as to induce tumoricidal activity (see for example Rollins,
Mol. and Cell. Biol.
11:3125-31(1991) and Walter, (1991)
Int. J. Cancer
49:431-35. MCP-1 has been implicated in mediating monocytic infiltration of tissues in inflammatory processes such as rheumatoid arthritis and alveolitis (see for example Koch, (1992)
J. Clin. Invest.
90:772-79 and Jones, (1992)
J. Immunol.
149:2147-54). Existing data suggest that MCP-1 may play an important role in the recruitment of monocyte-macrophages to atherosclerotic lesions (see for example, Nelken, (1991)
J. Clin. Invest
88:1121-27, Yla-Herttuala, (1991)
Proc. Nat'l. Acad. Sci
. USA 88:5252-56 and Cushing, (1990)
Proc. Natl. Acad. Sci
. USA 87:5134-38). In animal models, MCP-1 has been shown to be expressed in the brain after focal ischemi
Salari Hassan
Saxena Geeta
Tudan Christopher R.
Bozicevic, Field & Francis
Chemokine Therapeutics Corporation
Field Bret E.
Spivack Phyllis G.
LandOfFree
Therapeutics for chemokine mediated diseases does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Therapeutics for chemokine mediated diseases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutics for chemokine mediated diseases will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3273100