Antioxidant nitroxides and nitrones as therapeutic agents

Details Antioxidant nitroxides and nitrones as therapeutic agents Antioxidant nitroxides and nitrones as therapeutic agents

2002-04-02

2004-04-06

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S297000, C564S300000, C560S024000, C560S048000, C562S433000, C514S480000, C514S484000, C514S534000, C514S568000, C514S644000, C514S645000

Reexamination Certificate

active

06717012

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel compounds, compositions, and methods for the treatment and/or prevention of neurological, inflammatory, neuropsychiatric and aging-related disorders that result primarily from the overproduction of nitric oxide and other free radicals.
BACKGROUND OF THE INVENTION
Oxygen is vital to most human and animal life. It can, however, give rise to a variety of reactive oxygen species (“ROS”) as part of normal metabolism. Reactive species are produced by the body under normal conditions, and indeed are part of normal metabolism. The body is equipped with a variety of mechanisms which render ROS inactive.
Under normal conditions, the rate of ROS production does not exceed the capacity of the tissue to catabolize them. However, under certain conditions, ROS levels are raised beyond the capacity of these protective mechanisms (e.g., irradiation, environmental factors, iron loading, etc.) or when these mechanisms are faulty (e.g., genetic defects), and the ROS can cause cellular and tissue damage leading to a variety of diseases and even death. Proteins, lipids, and DNA are all substrates for ROS attack. It has been calculated that for every 100 tons of oxygen consumed two tons form reactive oxygen species. For every 10
12
oxygen molecules entering a cell each day {fraction (1/100)} damages protein and {fraction (1/200)} damages DNA. It is this damage to DNA, proteins, and lipids that makes the reactive oxygen species so dangerous, especially when the body's natural defenses are compromised.
Increasing evidence suggests that oxidative stress plays an important role in aging. The level of some antioxidant enzymes such as sodium oxide dismutase (SOD) and antioxidants such as uric acid, beta-carotene and vitamin E have a positive correlation with the life-span of species. Namely, the level decreases from human to chimpanzee to mouse (Culter,
Free Radicals in Biology
, vol. 4: p. 371, 1984). One hypothesis is that cells are damaged by free radicals and the damaged cells cannot function properly. The accumulation of damages to cells leads to aging (Culter, Id.). Another hypothesis is that free radicals cause cells to dysdifferentiate from their proper state of differentiation. This dysdifferentiation of cells leads to aging and all kinds of age-related diseases. (Culter, Id.). In spite of the disagreement on the mechanism of aging by those skilled in the art, it is clear that free radicals cause aging and age-related diseases. Free radicals have been implicated in stroke, ischemia-reperfusion, cardiovascular diseases, carcingogenesis and neurological diseases, including Alzheimer's disease, Parkinson's disease, dementia and Hodgkin's disease.
Complications of atherosclerosis, such as myocardial infarction, stroke and peripheral vascular disease account for half of the deaths in the United States. Arteriosclerosis begins with an injury to the endothelial cells and is associated with the proliferation of muscle cells inside the arteries. In the process of atherosclerosis, blood becomes thick and platelets, oxidized low density lipoprotein (LDL, the major lipid in LDL is cholesterol esters) and other substances begin to adhere to the walls of the arteries causing the formation of plaque. The oxidation of LDL is caused by free radicals. It was first recognized in 1969 (McCully,
Amer. J. Pathol.
56:111, 1969), and only recently rediscovered, that high level of plasma homocysteine is associated with an increased rate of death due to coronary artery disease (Nygard et al.,
N. Engl. J. Med.
24: 337, 1997; Graham et al.,
JAMA
277:1775, 1997). Homocysteine injures endothelial cells, thereby causing atherosclerosis through a number of mechanisms, including the generation of hydrogen peroxide (H
2
O
2
). It has been reported that homocysteine decreased the bioavailability of NO (not its production) and impaired the intracellular antioxidant enzymes, especially the glutathione peroxidases (Upchurch et al.,
J. Biol. Chem.
272: 17012, 1997). The key event in the process is generation and presence of free radicals. The increase of hydrogen peroxide (H
2
O
2
) can be a cause or a result. Homocysteine causes the production free radicals including superoxide (O
2
.−
) which reacts with NO causing its decreased bioavailability and the production of hydroxyl radical (.OH), or undergoes dismutation by SOD to produce hydrogen peroxide (H
2
O
2
). Hydrogen peroxide (H
2
O
2
) is further converted to the reactive hydroxyl radical (.OH) through the Fenton reaction and the metal-catalyzed Haber-Weiss reaction. The free radicals produced as a result of these reactions will damage the antioxidant enzymes which prevents the detoxification of free radicals. It is clear that scavenging free radicals will prevent the toxic effects of LDL and homocysteine and results in the prevention of atherosclerosis.
Extensive research efforts have been made to counter the damaging effects caused by free radicals which includes the use of antioxidant enzymes and antioxidants. Unfortunately, protein enzymes are too big to penetrate the cell wall and blood brain barrier. Antioxidants alone are not satisfactory for various reasons including the fact that they are consumed by free radicals and, thus, a large quantity is needed.
Several reactive oxygen species exist. Diatomic molecular oxygen (O
2
) readily reacts to form partially reduced species, which are generally short-lived and highly reactive and include the superoxide anion (O
2
.−
, a free radical), hydrogen peroxide H
2
O
2
and the hydroxyl radicals (.OH).
The ROS are the byproducts of mitochondrial electron transport, various oxygen-utilizing enzyme systems, peroxisomes, and other processes associated with normal aerobic metabolism as well as lipid peroxidation. These damaging byproducts further react with each other or other chemicals to generate more toxic products. For example, hydrogen peroxide H
2
O
2
can be transformed to the highly reactive hydroxyl radical (.OH) through the Fenton reaction and the metal catalyzed Haber-Weiss reaction:
Fe
2
+H
2
O
2
→Fe
3+
+ONOO
−
(Fenton reaction)
O
2
.−
+H
2
O
2
→.OH+OH
−
+O
2
(Fe
3+
/Fe
2+
catalyzed Haber-Weiss reaction)
Superoxide (O
2
.−
) reacts with nitric oxide (NO) to form the toxic peroxynitrite (ONOO
−
) which further decomposes to release the hydroxyl radical (.OH).
O
2
.−
+NO→ONOO
−
→NO
2
.
+.OH
Human beings have a defense system against toxic byproducts of metabolism including enzymes such as superoxide dismutase (“SOD”), catalases, peroxidases and antioxidants such as vitamins (e.g., vitamin A, beta-carotene, vitamin C and vitamin E), glutathione, uric acid and other phenolic compounds. SOD catalyzes the conversion of superoxide (O
2
.−
) into hydrogen peroxide (H
2
O
2
) and oxygen (O
2
).
2H
+
+O
2
.−
+O
2
.−
→H
2
O
2
+O
2
(catalyzed by SOD).
Hydrogen peroxide (H
2
O
2
) can be transformed by catalases and peroxidases to oxygen (O
2
) and water.
2H
2
O
2
→O
2
+H
2
O (catalyzed by catalases and peroxidase)
Despite the high efficiency of the defense system, some of these damaging species escape. The escaped reactive oxygen species and their products react with cellular DNA, protein and lipid resulting in DNA damage and peroxidation of membrane lipids. The deleterious results caused by reactive oxygen species are termed oxidative stress which affects normal gene expression, cell differentiation (Culter,
Free Radicals in Biology
, vol. 4, p. 371, 1984; Culter,
Ann. New York Acad. Sci.
621: 1, 1991) and leads to cell death. Oxidative stress is now considered to be responsible for many health problems like cardiovascular and neurological diseases, cancer and other aging-related diseases as well as the human aging process.
Receptors to the neuroexcitatory amino acid, glutamate, particularly the N-methyl-D-aspartate (NMDA) subtype of these receptors, play cr

Affiliated with

Also associated with

Rating

Antioxidant nitroxides and nitrones as therapeutic agents does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Antioxidant nitroxides and nitrones as therapeutic agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antioxidant nitroxides and nitrones as therapeutic agents will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3252311