Flavones as inducible nitric oxide synthase inhibitors,...

Details Flavones as inducible nitric oxide synthase inhibitors,... Flavones as inducible nitric oxide synthase inhibitors,...

2000-10-20

2004-10-19

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S025000, C514S456000, C514S453000, C514S465000

Reexamination Certificate

active

06806257

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to a method for inhibiting either iNOS or COX-2, or both in mammals using flavone compounds. The present invention is also directed to a method of activating K
+
channels in mammals; as well as methods for treating septic shock, treating or preventing aneurysm, inhibiting expression of angiotensin converting enzyme and reducing inflammation and related pathological changes using these compounds. Presently preferred compounds are oroxylin A (5,7-dihydroxy-6-methoxy flavone) and wogonin (5,7-dihydroxy-8-methoxy flavone).
BACKGROUND OF THE INVENTION
COX-2
Septic shock and multiple-organ failure are catastrophic consequences of an invasive infection. Septic shock has been estimated to occur in more than 500,000 cases per year in the United States alone. Septic shock is the most common cause of death in non-coronary intensive care units. As more antibiotic-resistant strains of bacteria evolve, the incidence of septic shock is expected to increase. Overall mortality rates from septic shock range from 30% to 90%. Aggressive antibiotic treatment and timely surgical intervention are the main therapies, but in many cases are insufficient. The search for new drug therapies has not been successful. For example, only small, but not statistically significant improvements in 28-day mortality compared to placebo was found when the compound Deltibant was administered to human patients suffering systemic inflammatory response syndrome and presumed sepsis (R. Stone,
J. Am. Med Assoc.,
vol. 277, pp. 482-487 (1997)).
Lipopolysaccharide (LPS) is believed to be the principal agent responsible for inducing sepsis syndrome, which includes septic shock, systemic inflammatory response syndrome, and multi-organ failure. Sepsis is a morbid condition induced by a toxin, the introduction or accumulation of which is most commonly caused by infection or trauma. The initial symptoms of sepsis typically include chills, profuse sweating, irregularly remittent fever, prostration and the like; followed by persistent fever, hypotension leading to shock, neutropenia, leukopenia, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiple organ failure.
LPS, also know as endotoxin, is a toxic component of the outer membrane of Gram-negative microorganisms (e.g.,
Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa
). Compelling evidence supports the toxic role of LPS; all pathophysiological effects noted in humans during Gram-negative sepsis can be duplicated in laboratory animals by injection of purified LPS. The mechanism by which LPS activates responsive cells is complex and not fully understood. The host response to Gram-negative bacterial infection depends on effector cell recognition of the bacteria, LPS, or both and involves both serum proteins and cell membrane receptors. When bacteria and LPS are removed via endocytosis and phagocytosis by reticuloendothial cells, concomitant activation of the host immune response by LPS results in the secretion of cytokines by activated macrophages, which in turn can trigger the exaggerated host responses associated with septic shock.
The normal immune response begins when neutrophils squeeze through the blood-vessel walls searching for bacterial pathogens in the surrounding tissue. Neutrophils can kill bacteria directly by releasing toxic chemicals or enzymes, such as elastase or collagenase. The neutrophils also attract other leukocytes to the area, including lymphocytes, macrophages, and monocytes, the last two of which release powerful immune-response activators called cytokines. The cytokines, in turn, stimulate more immune cell activity and increase the number of cells coming to the area by making the blood-vessel wall more permeable. Then, as the number of bacteria decreases, other cytokines signal to bring the normal immune response to an end.
If the cutoff mechanism fails, however, sepsis can begin. In sepsis, humoral and cellular mediators cascade in a process that becomes at least temporarily independent of the underlying infection. Excess neutrophils and macrophages are drawn to the site of infection, releasing excess immune-stimulating cytokines, eventually triggering the release of substances that damage the blood-vessel wall. More monocytes and macrophages come to the site and release more cytokines. Eventually, the blood vessels are so damaged and leaky that blood pressure falls and the blood can no longer supply nutrients to the body's organs. Entire organs can begin to shut down. Many patients die after losing the function of two or more organs.
Two cytokines that play an important role in sepsis are interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF alpha). These two polypeptides can raise body temperature, increase the expression for adhesion molecules on neutrophils and endothelial cells (promoting adhesion of leukocytes), stimulate the production of vasodilating prostaglandins (thus increasing the permeability of blood vessels), trigger the release of other cytokines, stimulate neutrophils, and activate fibroblasts. All these processes enhance the probability of organ failure seen in severe septicemia. Drug therapies that target only one of these two cytokines have proved ineffective (See Stone). Drug therapies that are effective against general inflammatory responses have not proven to be effective against the cascading acute inflammation that produces septicemia. There is a need for drugs that can inhibit this cascading system at the beginning steps of production of IL-1 and TNF alpha.
Other important cytokines, chemokines, and other proteins having proinflammatory activity include interferon-gamma (IFN gamma), interleukin-6 (IL-6), macrophage chemotactic protein (MCP), inducible nitric oxide synthetase (iNOS), mitogen-activated protein kinases (MAPKs), macrophage inflammatory protein, KC/CINC (growth related gene), tissue factor (TF), granulocyte-macrophage-colony stimulating factor (Gm-CSF) and phosphotyrosine phosphatase (PTPase).
Prostaglandins are also involved in the proinflammatory response; e.g., prostaglandins increase the permeability of the blood-vessel wall. Cyclooxygenase (COX; prostaglandin endoperoxide synthase) catalyzes the conversion of arachidonic acid to prostaglandin (PG) endoperoxide (PGH2), which is the rate limiting step in prostaglandin biosynthesis. Two isoforms of COX have been cloned from animal cells: the constitutively expressed COX-1, and the mitogen-inducible COX-2. Prostaglandins produced as a result of the activation of COX-1 may have physiological functions such as the antithrombogenic action of prostacyclin released by the vascular endothelium, and the cytoprotective effect of PGs produced by the gastric mucosa. However, COX-2 is the enzyme expressed following the activation of cells by various proinflammatory agents including cytokines, endotoxin and other mitogens. These observations suggest that COX-2 instead of COX-1 may be responsible for inducing production of the prostaglandins involved in inflammation. Only a few pharmacological agents that suppress the expression of COX-2 without affecting COX-1 have been identified, for example, glucocorticoids and radicicol. However, these agents have undesirable side effects.
There is a need for compounds that selectively inhibit COX-2, and that act as potent anti-inflammatory agents, with minimal side effects. To prevent septicemia, such a compound should also inhibit the production of a wide variety of proinflammatory cytokines, especially TNF alpha and IL-1, chemokines, and protein-tyrosine kinases.
Nitric Oxide (NO) was originally identified in vascular endothelial cells (Palmer et al. (1987)
Nature
327:524-526 and Palmer et al.(1988)
Nature
333:664-666) and has been identified as being identical to endothelium-derived relaxing factor (Moncada et al. (1989)
Biochem. Pharmacol.
38:1709-1715; Furchgott (1990)
Acta Physiol. Scand.
139:257-270 and Iganarro (1990)
Annu. Rev. Phamacol. Toxicol.
30:535-560). Besides endothelial cells, NO formatio

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