Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-12-14
2003-04-22
Vollano, Jean F. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S022000, C562S405000, C562S433000, C562S444000, C514S534000
Reexamination Certificate
active
06552076
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to compounds for treating diseases by altering mitochondrial function that affects cellular processes, as well as to compositions and methods related thereto.
2. Description of the Related Art
Mitochondria are the subcellular organelles that are the main energy source in cells of higher organisms, and provide direct and indirect biochemical regulation of a wide array of cellular respiratory, oxidative and metabolic processes. The electron transport chain (ETC) machinery resides in the mitochondrion, and drives oxidative phosphorylation to produce metabolic energy in the form of adenosine triphosphate (ATP). Mitochondria also play a critical role in maintaining intracellular calcium homeostasis. In addition to their role in energy production in growing cells, mitochondria (or, at least, mitochondrial components) are required for at least some forms of programmed cell death (PCD), also known as apoptosis (Newmeyer et al.,
Cell
79:353-364, 1994; Liu et al.,
Cell
86:147-157, 1996). Apoptosis is required for normal development of the nervous system and functioning of the immune system. However, some disease states are thought to be associated with either insufficient or excessive levels of apoptosis (e.g., cancer and autoimmune diseases in the first instance, and stroke damage and neurodegeneration in Alzheimer's disease in the latter case). For general reviews of apoptosis, and the role of mitochondria therein, see Green and Reed (
Science
281:1309-1312, 1998), Green (
Cell
94:695-698, 1998) and Kroemer (
Nature Medicine
3:614-620, 1997).
Defective mitochondrial activity, including but not limited to failure at any step of the elaborate multi-complex mitochondrial assembly, known as the electron transport chain (ETC), may result in (i) decreases in ATP production, (ii) increases in the generation of highly reactive free radicals (e.g., superoxide, peroxynitrite and hydroxyl radicals, and hydrogen peroxide), (iii) disturbances in intracellular calcium homeostasis and (iv) the release of factors that initiate the apoptosis cascade. Because of these biochemical changes, mitochondrial dysfunction has the potential to cause widespread damage to cells and tissues. For example, oxygen free radical induced lipid peroxidation is a well established pathogenic mechanism in central nervous system (CNS) injury such as that found in a number of degenerative diseases, and in ischemia (i.e., stroke).
Cells from long-lived tissue that have high energy demands such as neurons, pancreatic islet cells, cardiac and muscle cells are particularly vulnerable to mitochondrial dysfunction. A number of degenerative diseases may thus be caused by or associated with either direct or indirect alterations in mitochondrial function. These include Alzheimer's Disease, diabetes mellitus, Parkinson's Disease, neuronal and cardiac ischemia, Huntington's disease and other related polyglutamine diseases (spinalbulbar muscular atrophy, Machado-Joseph disease (SCA-3), dentatorubro-pallidoluysian atrophy (DRPLA) and spinocerebellar ataxias, dystonia, Leber's hereditary optic neuropathy, schizophrenia, and myodegenerative disorders such as mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS), and myoclonic epilepsy ragged red fiber syndrome (MERRF).
Increasing evidence points to the fundamental role of mitochondrial dysfunction in neurodegenerative diseases (Beal,
Biochim. Biophys. Acta
1366: 211-223, 1998), and recent studies implicate mitochondria for regulating the events that lead to necrotic and apoptotic cell death (Susin et al.,
Biochim. Biophys. Acta
1366: 151-168, 1998). Stressed (stressors include free radicals, high intracellular calcium, loss of ATP, among others) mitochondria may release pre-formed soluble factors that can initiate apoptosis through an interaction with novel apoptosomes (Marchetti et al.,
Cancer Res.
56:2033-38, 1996; Li et al.,
Cell
91: 479-89, 1997). Release of preformed soluble factors by stressed mitochondria, like cytochrome c, may occur as a consequence of a number events. In some cases, release of apoptotic molecules (apoptogens) occurs when mitochondria undergo a sudden change in permeability to cytosolic solutes. This process has been termed “permeability transition”. There is strong evidence that suggests that the loss of mitochondrial function may be due to the activation of the mitochondrial permeability transition pore, a Ca
2+
regulated inner membrane megachannel. Opening of the mitochondrial permeability transition pore results in the exchange of solutes that are less than 1500 daltons in size, collapse of the mitochondrial membrane potential, and uncoupling of the electron transport chain. In other cases, the permeability may be more subtle and perhaps more localized to restricted regions of a mitochondrion. In still other cases, overt permeability transition may not occur but apoptogens can still be released as a consequence of mitochondrial abnormalities. The magnitude of stress (ROS, intracellular calcium levels) influences the changes in mitochondrial physiology that ultimately determine whether cell death occurs via a necrotic or apoptotic pathway. To the extent that apoptotic cell death is a prominent feature of degenerative diseases, mitochondrial dysfunction may be a critical factor in disease progression.
Whereas mitochondria-mediated apoptosis may be critical in degenerative diseases, it is thought that disorders such as cancer involve the unregulated and undesirable growth (hyperproliferation) of cells that have somehow escaped a mechanism that normally triggers apoptosis in such undesirable cells. Enhanced expression of the anti-apoptotic protein, Bcl-2 and its homologues is involved in the pathogenesis of numerous human cancers. Bcl-2 acts by inhibiting programmed cell death and overexpression of Bcl-2 and the related Bcl-xL block mitochondrial release of cytochrome c from mitochondria and the activation of caspase 3 (Yang et al,
Science
275:1129-1132, 1997; Kluck et al.,
Science
275:1132-1136, 1997; Kharbanda et al.,
Proc. Natl. Acad. Sci. USA
94:6939-6942, 1997). Bcl-2 also binds to several proteins that are involved in death regulation (Reed,
Nature
387:773-779, 1997). Over expression of Bcl-2 and Bcl-xL protect against the mitochondrial dysfunction preceding nuclear apoptosis that is induced by chemotherapeutic agents. In addition, acquired multi-drug resistance to cytotoxic drugs is associated with inhibition cytochrome c release that is dependent on overexpression of Bcl-xL (Kojima et al.,
J. Biol. Chem.
273: 16647-16650, 1998). Because mitochondria have been implicated in apoptosis, it is expected that agents that interact with mitochondrial components will effect a cell's capacity to undergo apoptosis. Thus, agents that induce or promote apoptosis in hyperproliferative cells are expected to be useful in treating such hyperproliferative disorders and diseases.
Thus, alteration of mitochondrial function has great potential for a broad-based therapeutic strategy for designing drugs to treat degenerative diseases as well as hyperproliferative diseases. The mitochondrial permeability transition pore is a key target for the prevention of mitochondrial function collapse that leads to cell death, or the induction of apoptosis in cancer cells via dysregulation of mitochondria. This megachannel is a multi-protein complex in which the adenine nucleotide translocator (ANT) has been implicated as the critical molecular component.
ANT is located in the inner mitochondrial inner membrane and it facilitates transport of ADP and ATP across the mitochondrial inner membrane. In humans there are three genetic isoforms (ANT1, ANT2 and ANT3), each with different tissue expression patterns. ANT1 is highly expressed in heart and skeletal muscle and is induced during myoblast differentiation. ANT2 is overexpressed in a variety of hyperproliferative cells, tumors and neoplastically transformed cells with high glycol
Ghosh Soumitra S.
Moos Walter H.
Pei Yazhong
MitoKor
Seed IP Law Group PLLC
Vollano Jean F.
LandOfFree
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