Epoxide hydrolase inhibitor methods

Details Epoxide hydrolase inhibitor methods Epoxide hydrolase inhibitor methods

1999-05-14

2001-01-16

Gitomer, Ralph (Department: 1623)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving hydrolase

C435S069200

Reexamination Certificate

active

06174695

ABSTRACT:

FIELD OF THE INVENTION
The present invention generally relates to treating inflammatory conditions, such as adult respiratory distress syndrome (ARDS), and other acute inflammatory conditions, such as systemic inflammatory response syndrome (SIRS), and more particularly to methods of treating inflammatory diseases mediated by polyunsaturated lipid metabolites by inhibiting epoxide hydrolase, to methods for assaying or screening epoxide hydrolase inhibitors for toxicity, and methods for the analysis of metabolites of lipid metabolites as indicators of oxidative stress and disease states. The invention also includes as one aspect novel biologically active tetrahydrofuran diols of arachidonic acid (dihydroxy-oxy-eicosadienoates or DiHOxyEDEs).
This invention was made with Government support under Grant ES02710, awarded by the National Institutes of Health. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
Inflammation is signaled by redness, swelling, heat and pain as a reaction of the body against injury or assault. A variety of chemicals have been implicated as chemical mediators of the inflammatory reaction, including histamine, kinins, prostaglandins, platelet-activating factors, leukotrienes, and, from nerve endings, substance P. Mediators of the acute inflammatory reaction seem to play roles in one or more of increasing vascular permeability, attracting leukocytes, producing pain, local edema and necrosis.
The inflammatory response is one of the most important physiological mechanisms for the maintenance of human health. However, disorders of inflammation or an inappropriate inflammatory response can result in tissue injury, morbidity, or mortality.
Swelling is a characteristic inflammatory response of tissues to injury. Swelling is produced by leakage of water and solutes of the blood directly into the tissue matrix. The increased leakiness of blood vessels after injury may be due to direct damages of blood vessels or may occur after the release of substances such as histamine (inflammatory mediators) that open up gaps between endothelial cells that line the blood vessels. These and other inflammatory signals can act directly on leukocytes leading to their attachment to the walls of blood vessels, a change in leukocyte morphology, and movement through the wall of the vessel into the tissues. A mild degree of swelling (or edema) does not affect the functional integrity of injured tissues (except perhaps in the brain), but, in severe injuries, massive swelling distorts tissue architecture, impedes the delivery of oxygen to cells, and causes extensive fluid loss from the vascular compartment.
Inflammation is also involved in various chronic conditions, such as asthma, although it is not presently clear which inflammatory cells or which particular mediators are significantly involved in asthma.
Adult respiratory distress syndrome (ARDS) is a pulmonary disease that has a mortality rate of 50% and results from lung lesions that are caused by a variety of conditions found in trauma patients and in severe burn victims. Ingram, R. H. Jr., “Adult Respiratory Distress Syndrome,”
Harrison's Principals of Internal Medicine
, 13, p. 1240, 1995. With the possible exception of glucocorticoids, there have not been therapeutic agents known to be effective in preventing or ameliorating the tissue injury, such as microvascular damage, associated with acute inflammation that occurs during the early development of ARDS.
ARDS, which is defined in part by the development of alveolar edema, represents a clinical manifestation of pulmonary disease resulting from both direct and indirect lung injury. While previous studies have detailed a seemingly unrelated variety of causative agents, the initial events underlying the pathophysiology of ARDS is not well understood. ARDS was originally viewed as a single organ failure, but is now considered a component of the multisystem organ failure syndrome (MOFS). Pharmacologic intervention or prevention of the inflammatory response is presently viewed as a more promising method of controlling the disease process than improved ventilatory support techniques. See, for example, Demling, Annu.
Rev. Med
., 46, pp. 193-203, 1995.
Another disease (or group of diseases) involving acute inflammation is the systematic inflammatory response syndrome, or SIRS, which is the designation recently established by a group of researchers to describe related conditions resulting from, for example, sepsis, pancreatitis, multiple trauma such as injury to the brain, and tissue injury, such as laceration of the musculature, brain surgery, hemorrhagic shock, and immune-mediated organ injuries. Bone,
JAMA
, 268:24, pp. 3452-3455, 1992.
U.S. Pat. No 5,504,111, inventors Falvin et al., issued Apr. 2, 1996, suggests use of 2,3-alkylcarbonyloxybenzoic acid in treating ARDS. The patentees suggest a use for their invention is also in the therapeutic treatment and/or prevention of sepsis and septic shock because many of the physiological and, indeed, the pathological processes involved with ARDS have also been demonstrated to be involved in the condition of sepsis and septic shock.
U.S. Pat. No. 5,488,033, inventor Wei, issued Jan. 30, 1996, discloses treatments with corticotropin-releasing factor as being useful in systemic inflammatory conditions such as SIRS, when such are characterized by vascular leakage, by suppressing such vascular leakage.
U.S. Pat. No. 5,455,271, issued Oct. 3, 1995, inventors Yuan et al., discloses inhibitors of leukotriene A
4
hydrolase. This metaloprotein hydrolase is said to exhibit inhibition of both epoxide hydrolase and aminopeptidase activities. The patent suggests that selective inhibitors of LTA4 hydrolase are of interest as potential anti-inflammatory agents. The patent discloses a class of transition state analog inhibitors based on the proposed mechanism of the aminopeptidase activity and the natural substrate structure of the LTA4 hydrolase enzyme.
U.S. Pat. No. 5,530,114, issued June 25, 1996, inventors Bennett et al., discloses methods of treating diseases amendable to modulation of the synthesis or metabolism of arachidonic acid by providing anti-sense oligonucleotides capable of inhibiting the function of RNA encoding proteins involved in the synthesis and metabolism of arachidonic acid and related compounds. In particular, various of the leukotrienes resulting from an oxidative pathway (the lipoxygenase pathway) are discussed.
SUMMARY OF THE INVENTION
In one aspect of the present invention, a method for treating inflammatory diseases, particularly adult respiratory distress syndrome (ARDS), is provided which comprises administering to a patient in need of therapy an effective therapeutic amount of an epoxide hydrolase inhibitor.
Aspects of the invention generally relate to our discovery that the diol metabolite of linoleate appears to lead to ARDS symptoms and to increase inflammation. Accordingly, an aspect of the invention is for treatments by means of drugs that inhibit formation of leukotoxin and leukotoxin diol, which drugs include epoxide hydrolase inhibitors such as chalcone oxides, lipid alkoxides, glycidols, and diimides, or by treating the inflammation (caused by leukotoxin diol) by means of THF-diols of an arachidonate, which act in an anti-inflammatory manner. More particularly, the administered epoxide hydrolase inhibitor retards or prevents an inflammatory response in a patient via an inhibition of formation of one or more polyunsaturated lipid metabolites. For example, the administering is effective to inhibit the formation of one or more dihydroxy-oxy-eicosadienoates, or DiHOxyEDEs in the arachidonic acid series of oxylipins, the leukotoxin diols in the linoleaic acid series, or other lipid diols including tetrahydrofuran diols.
The art has up to now viewed leukotoxin, or cis-9,10-epoxyoctadec-12(Z)-enoic acid, as being the agent causing the toxic responses characterized by ARDS due to its presence in skin and plasma of such patients. Leukotoxin and isoleukotoxin (cis-9,10-epoxyoctadec-12(Z)-

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