Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-07-26
2002-11-12
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06479546
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of this invention is lipoxygenase inhibitors.
2. Background of the Invention
Lipoxygenase are a structurally related family of nonheme iron deoxygenases that function in the production of fatty acid hydroperoxides. The lipoxygenases are present in a wide variety of organisms and catalyze the oxidation of unsaturated fatty acids utilizing an essential, non-heme iron atom. The generally accepted mechanism for lipoxygenases involves a hydrogen atom abstraction at C-3 of the 1,4-diene by Fe(III), with subsequent trapping of the pentadienyl radical by oxygen, forming the hydroperoxide product. In humans, the 5S-, 12S- and 15S-lipoxygenases oxygenate arachidonic acid in different positions along the carbon chain, e.g., as seen in leukotriene synthesis.
Lipoxygenase activity plays a critical role in asthma, atherosclerosis and cancer regulation, among other physiological processes and conditions. As such, the inhibition of lipoxygenase (LO) is currently an important goal of bio-medical research. To date, a number of different types of lipoxygenase inhibitors have been identified.
However, there is continued interest in the identification of additional lipoxygenase inhibitors.
Relevant Literature
U.S. Patents of interest include: U.S. Pat. Nos. 4,645,627 and 5,037,992. Also of interest are: Lewis et al., J. Am. Chem. Soc. (1999) 121: 1395-1396; Sailer et al., Eur. J. Biochem. (1998) 256: 364-368; and Wang et al., Biochemistry (1993) 32: 1500-1509.
SUMMARY OF THE INVENTION
Allosteric inhibitors of lipoxygenase and methods for their use are provided. In many embodiments, the allosteric inhibitors are sulfated long chain alkenyl compounds. The compounds of these embodiments are long chain monounsatured alkenyl compounds having a single sulfate moiety at the 1 position. In many embodiments, the subject compounds range in length from about 14 to 22 carbon atoms and the site of unsaturation is located between the 8 and 14 positions. Specific compounds of interest include 9-oleyl sulfate; 9-palmitoleyl sulfate and 11-eicosenyl sulfate. The subject compounds exhibit lipoxygenase inhibitory activity. As such, the subject compounds find use in treating disease conditions characterized by the presence of undesirable lipoxygenase activity. Also provided are pharmaceutical preparations of the subject compounds.
DEFINITIONS
The term “lipoxygenase” is used to refer to a protein that catalyzes the oxidation of unsaturated fatty acids utilizing an essential, non-heme iron atom. Specific lipoxygenases of interest include, but are not limited to: soybean lipoxygenase-1; 15-human lipoxygenase; 12-human lipoxygenase; 5-human lipoxygenase; 9-human lipoxygenase; and the like.
The term “allosteric inhibitor” refers to a compound that inhibits lipoxygenase activity through binding to the allosteric binding site of the lipoxygenase protein.
“Alkenyl” means a linear monovalent hydrocarbon chain containing at least one double bond.
“Long chain” means a chain having a length of from about 14 to 22 carbon atoms in length.
“Monounsaturated” means a single site of unsaturation, e.g., a single double-bond between two carbon atoms in a compound.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Allosteric lipoxygenase inhibitors and methods for their use in lipoxygenase inhibition are provided. In many embodiments of the subject invention, the inhibitors are sulfated long chain alkenyl compounds. The compounds of this embodiment are generally long chain monounsatured alkenyl compounds having a single sulfate moiety at the 1 position. In many embodiments, the subject compounds range in length from about 14 to 22 carbon atoms and the site of unsaturation is located between the 8 and 14 positions. Specific compounds of interest include 9-oleyl sulfate; 9-palmitoleyl sulfate and 11-eicosenyl sulfate. The subject compounds exhibit lipoxygenase inhibitory activity. As such, the subject compounds find use in treating disease conditions characterized by the presence of undesirable lipoxygenase activity. Also provided are pharmaceutical preparations of the subject compounds. In further describing the subject invention, the subject compounds will be described first in greater detail, followed by a review of methods for their use in the lipoxygenase inhibition.
Before the subject invention is further described, it is to be understood that the invention is not limited to the particular embodiments of the invention described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present invention will be established by the appended claims.
In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.
Allosteric Lipoxygenase Inhibitors
As summarized above, the subject methods employ allosteric inhibitors of lipoxygenase. By allosteric inhibitor of lipoxygenase is meant a compound that binds to the allosteric binding site of lipoxygenase and at least slows, if not substantially stops, the lipoxygenase activity. As the subject compounds exhibit lipoxygenase inhibitory activity, in many embodiments the compounds exhibit a K
1
value of from about 0.05 to 1.5 &mgr;m, and usually from about 0.10 to 1.0 &mgr;m.
Allosteric lipoxygenase inhibitors employed in the subject invention are, in many embodiments, small molecule compounds. As the inhibitors of these embodiments are small molecules, they have a molecular weight that generally ranges from about 200 to 600, usually from about 250 to 500 and more usually from about 250 to 400 daltons.
In many embodiments of the subject invention, the allosteric lipoxygenase inhibitors employed in the subject methods are sulfated long chain alkenyl compounds. By sulfated long chain alkenyl compound is meant a long chain molecule of from about 14 to 22 carbon atoms in length, where in many embodiments the number of carbon atoms in the long chain of the compounds is between 16 and 20, e.g., 16, 18 or 20. The subject compounds of this embodiment exhibit good water solubility, where their solubility typically ranges from about 150 to 200 &mgr;m, usually from about 125 to 150 &mgr;m and more usually from about 75 to 100 &mgr;m. In addition, the subject compounds exhibit increased potency as compared to their carboxylic analogs (i.e., molecule which is the same as the subject molecule except that the sulfate moiety is replaced with a caboxylate moiety), where the magnitude of this increased potency typically ranges from about 30 to 50 fold.
As the subject compounds are alkenyl compounds, they include at least one site of unsaturation. In many embodiments, the at least one site of unsaturation is in the form of a carbon-carbon double bond. While there may be more than one site of unsaturation, in many embodiments, the compounds are monounsaturated alkenyl compounds, having a single site of unsaturation, e.g., a single carbon-carbon double bond. The site of monounsaturation typically lies between atoms 6 and 14, usually between atoms 7 and 13 and more usually between atoms 8 and 12 in the long chain alkenyl moieties of the compounds. Preferred sites of monounsaturation are positions 9 and 11 in many embodiments.
As summarized above, the subject compounds are sulfated compounds, by which is meant that they exhibit a sulfate moiety. The term “sulfate moiety” is used to refer not only to —SO
3
H but also ionized and salt forms thereof, e.g., —SO
3
—; —SO
3
Na; etc. In general, the subject compounds include a single sulfate moiety located at the terminal 1 position of the compounds.
In certain embodiments of the subject invention, the employed compound are des
Holman Theodore Russell
Mogul Rakesh
Bozicevic, Field & Francis
Field Bret E.
The Regents of the University of California
Weddington Kevin E.
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