Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2001-03-12
2004-10-19
Fay, Zohkeh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S739000, C514S546000
Reexamination Certificate
active
06806293
ABSTRACT:
FIELD OF THE INVENTION
The present invention is generally directed to compounds having mitogen-activated protein kinase modulating activity, and to methods of screening such compounds and to compositions employing the same. Modulation of mitogen-activated kinase activity has been associated with the treatment of a variety of medical diseases, conditions, and/or symptoms thereof in warm-blooded animals including humans.
BACKGROUND OF THE INVENTION
Intercellular communication is essential for the development and normal function of all multicellular organisms. Cells communicate and respond to extracellular signals by utilizing various cellular mechanisms called signal transduction pathways. These pathways involve a series of molecular events culminating in the activation of effector mechanisms that result in specific cellular responses. Certain disturbances in signal transduction pathways are involved in the pathogenesis of various diseases, conditions and symptoms thereof including cancer, cardiovascular disease, inflammation, autoimmune diseases (e.g. rheumatoid arthritis), neurodegenerative diseases (e.g. Alzheimer's disease), and other diseases including acquired immune deficiency syndrome (AIDS) and the like.
One of the important signal transduction pathways is the mitogen-activated protein (MAP) kinase pathway. This pathway is essential in cellular growth and differentiation. It is known that blockage of the MAP kinase pathway suppresses tumor growth. In this signal transduction cascade, sequential activation of kinases and subsequent protein phosphorylation lead to the activation of transcription factors at the DNA level.
The sequential activation of kinases (also known as the protein kinase cascades) is a common mechanism of signal transduction in many cellular processes. Mitogen-activated protein kinases are believed to include up to five levels of protein kinases that sequentially activate each other through the process of phosphorylation. Among several mechanisms for activating these cascades, one is believed to be initiated by a small GTP binding protein which transmits the signal to the protein kinases. The signal is then transmitted down the cascade by enzymes at the various levels. The existence of multiple levels in each of the MAP kinase cascades is believed essential for signal amplification, specificity and tight regulation of the transmitted signals.
Nicholas S. Duesbery et al.,
Nature Medicine
, Vol. 5/7 (July, 1999) report that tumor cells proliferate and spread throughout the body in apparent disregard of normal environmental cues. The inhibition of the mitogen-activated protein kinase signal transduction pathway enables tumor cells to revertto a non-transformed phenotype and bypass the arrest of tumor growth in the body. It is also known that many oncogenes activate the mitogen-activated protein kinase signal transduction pathway and it is this inappropriate activation that mediates the transformed phenotype.
The pathophysiology of many diseases involves dysfunctional intercellular signaling. As indicated above, in cancer, for example, some oncogenes encode signal transduction pathway proteins involved in the regulation of self proliferation. Expression of these oncogenes may induce chronic activation that results in uncontrolled proliferation. Thus, tumor cells are effectively released from normal regulation and thereby proliferate, enabling the tumor to enlarge. In conditions manifesting unstable angina and myocardial infarction, platelets aggregate and participate in the occlusion of coronary arteries by responding to a variety of signals released by the rupture of an atherosclerotic plaque. In this particular case, platelets actually respond appropriately to signals they are receiving, but they do so in an inappropriate place.
In autbimmune disease, signaling molecules produced by the processing and presentation of self-antigens activate cells of the immune system, and the activated immune cells respond by eliminating the offensive stimulus. Cells in the body that express the self-antigen are targeted for destruction, and once the function of these normal cells is compromised, symptoms of the autoimmune disease become evident.
Since the pathogenesis of many diseases can be traced to a dysfunction in intercellular signaling, compounds which modulate the signal pathway can have utility in the treatment of a variety of such diseases.
Pheromones are a class of chemicals that are communicative between animals of the same species and elicit stereotypical behavior and endocrine responses. Although there is a wide variety and a large number of pheromone chemical structures, a single pheromone molecule has been shown to have biological effects in non-associated species such as a species of insects and elephants. Some chemical similarities exist between pheromones at different species.
The term “invertebrate pheromone” (or “pheromone”) in the context of the present invention should be understood as encompassing any chemical compound isolated from any invertebrate species which is produced and discharged from glands and external ducts and functions by influencing other members of the same species in one of the ways known in the art, and which possesses mitogen-activating protein (MAP) kinase modulation activity. One example of an invertebrate order are insects, one of the predominant species of insects being Lepidoptera.
The terms “pheromone” or “pheromone compound” encompasses the natural pheromones as well as synthetic compounds which display a similar MAP kinase modulating activity. Such synthetic compounds include various derivatives of the natural pheromones, as well as analogs thereof.
The pheromone communication system involves the release of specific chemicals from a pheromone producer (emitter), the transmission of these chemicals in the environment to a receiver, and the processing of the signals to mediate the appropriate behavioral responses in the receiver. Some pheromone compounds are believed to activate the vomeronasal organ (VNO) which resides interior to the main olfactory epithelium (MOE) in a blind-ended pouch within the septum of the nose. In both locations, the VNO and MOE neuroepithelial dendrites terminate in specialized cilia containing specific receptors that bind odorants. This binding initiates a cascade of enzymatic reactions that results in the production of messengers and the eventual depolarization of the cell membrane.
The signal transduction mechanisms through which pheromone compounds exert their effect involve various pathways which are commonly found in various other biological processes.
Applicants have investigated pheromone compounds as a class of chemicals that have potential modulating activity for the MAP kinase signal transduction pathway. The potential of active pheromone compounds to modulate (i.e. activate or inhibit) the MAP kinase signal transduction pathways provides compounds which may be used for the treatment of a wide variety of diseases, conditions, and symptoms thereof as mentioned above. For example, MAP kinase pathway inhibitors have been described 20 as effective in treating cancer and other proliferative diseases such as psoriasis and restenosis as disclosed in A. J. Bridges et al., U.S. Pat. No. 5,525,625. MAP kinase pathway inhibitors have also been described as being effective in abolishing resistance to myocardial infarction induced by heat stress in M. Joyeux et al., Cardiovasc. Drugs Ther., Vol.14/3, pp.337-343 (June, 2000). It is also known that MAP kinase pathway activators can desirably affect wound healing and tissue repair.
It would therefore be a significant advance in the art of treating diseases, conditions and symptoms thereof to identify pheromone compounds possessing MAP kinase modulating activity. It would also be a further advance in the art to identify pheromone compounds which have MAP kinase modulating activity because of their potential for use in treating a variety of diseases, conditions, and symptoms thereof including cancer, autoimmune disease, psoriasis, restenosis as w
Darley Pharmaceuticals LTD
Fay Zohkeh
Kwon Brian-Yong S.
Watov & Kipnes P.C.
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