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  Anti-inflammatory compositions and methodsUSPTO Application #: 20050272668Title: Anti-inflammatory compositions and methods Abstract: The disclosed invention includes pharmaceutical compositions and methods for treating inflammatory conditions, particularly those that are characterized by increased binding of alpha-9 integrin to one or more of its ligands. Also disclosed are methods for selecting compounds for use in such compositions and methods. (end of abstract)
Agent: Foley & Lardner LLP - Palo Alto, CA, US Inventors: Theodore A. Yednock, Michael A. Pleiss USPTO Applicaton #: 20050272668 - Class: 514019000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 2 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20050272668. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the benefit of U.S. Provisional Application No. 60/______, which was converted pursuant to 37 C.F.R. .sctn. 1.53(c)(2)(i) from U.S. patent application Ser. No. 08/904,424, filed Jul. 31, 1997, and of U.S. Provisional Application No. 60/054,453, filed Aug. 1, 1997, all of which applications are incorporated herein by reference in their entireties. FIELD OF THE INVENTION [0002] The invention relates to compositions that modulate binding of a specific integrin molecule, .alpha..sub.9.beta..sub.1, to its receptor(s), to methods of treatment using such compounds, and to screening assays suitable for identify additional modulatory compounds for use in such treatment methods. Pharmaceutical compositions which include such compounds are useful in treating inflammation and other disorders where modulation of .alpha..sub.9.beta..sub.1-receptor interactions is desirable. REFERENCES [0003] Hynes, R. O. (1987) Cell 48: 549-554. [0004] Palmer, E. L., et-al. (1993) J. Cell Biol. 123: 1289-1297. [0005] Smith, et al. (1996) J. Biol. Chem. 271: 28485. [0006] Yednock, T. A., et al. J. Biol. Chem., 1995, 270: 28740-28750. [0007] Yokosaki, et al. 1994, J. Biol. Chem. 269: 26691-26696. [0008] Yokosaki, et al. 1996, J. Biol. Chem. 271: 24144-24150. BACKGROUND OF THE INVENTION [0009] The integrins are a group of glycoproteins that are present on a wide variety of cells, where they mediate cell-cell and cell-matrix adhesion via interactions with receptors present on cell membranes or in the extracellular matrix. Known receptors for the various integrin family members include cell surface immunoglobulins, extracellular matrix proteins (laminin, collagen, fibronectin, tenascin), and cadherins. [0010] All known members of the integrin family are composed of two subunits, termed alpha and beta. There are currently at least sixteen recognized alpha subunits and eight different beta-subunits; integrins containing the .beta..sub.1 form of the beta subunit are known as the ".beta..sub.1 integrin family." Members of this family are expressed by a diverse distribution of tissues and exhibit specific binding specificities. Thus, .alpha..sub.1.beta..sub.1 integrin is expressed by T-lymphocytes and fibroblasts and binds to collagen and laminin; in contrast, .alpha..sub.4.beta..sub.1 integrin (VLA-4) is expressed by several types of hematopoietic cell and binds to VCAM-1, fibronectin and madCAM. It is therefore the alpha subunit that apparently confers receptor binding specificity to the protein. [0011] A relatively new member of the .beta..sub.1 integrin family, .alpha..sub.9.beta..sub.1 (also referred to herein as "alpha-9 integrin") has been shown to bind to tenascin and osteopontin, both of which are components of the extracellular matrix which are induced at sites of inflammation (Yokosaki; Smith). When sequences of the various alpha subunits were compared, alpha-9 integrin was shown to have the closest sequence identity to the alpha-4 subunit; however this represents only 39% sequence identity (Palmer). Moreover, the two subunits have different cell and tissue distributions. While .alpha..sub.9.beta..sub.1 is expressed on airway smooth muscle cells, and non-intestinal epithelial cells (Palmer), and diffusely on hepatocytes and basal keratinocytes (Yokosaki, 1994), .alpha..sub.4.beta..sub.1 integrin is present mainly on hematopoietic cells. [0012] Heretofore, there has been no definitive determination of an in vivo function for .alpha..sub.9.beta..sub.1 integrin, nor has a physiological consequence of disruption of .alpha..sub.9.beta..sub.1-rece- ptor interactions been identified, despite its presence in several tissues, as described above. Nor, despite its association with osteopontin and tenascin, has there been any reason to suspect that alpha-9 integrin might play a role in inflammatory disorders, since the .alpha..sub.9.beta..sub.1 molecule had not been associated with any of the hematopoietic cells commonly associated with this disorder. [0013] In studies carried out in support of the present invention, it is now now found that .alpha..sub.9.beta..sub.1 is present on neutrophils, a class of phagocytic cells which play an important role in inflammation. In humans, these cells are notable for their relative lack of alpha-4/beta-1 integrin. Therefore, the present invention provides basis for involvement of .alpha..sub.9.beta..sub.1 in acute inflammatory responses. [0014] Further differences among the .beta..sub.1-integrins are associated with their binding specificities or endogenous ligands. While they all bind one or more proteins or proteoglycans that form the extracellular matrix, each integrin family member exhibits a distinct molecular specificity which may dictate, in part, its physiological specificity. Thus, while alpha-4/beta-1 integrin is known to bind fibronectin and VCAM-1, alpha-9 integrin has been characterized as binding the matrix proteins osteopontin and tenascin (Yokosaki, 1994; Smith, 1996). According to a further discovery related to the present invention, alpha-9 integrin also binds VCAM-1, though, as discussed below, it is likely that such binding occurs at a site that distinct from the alpha-4 binding site. [0015] The present invention therefore provides basis for new therapeutic regimens directed at modulating alpha-9 integrin binding to its ligand(s), and in particular, those ligands which are involved in the inflammatory response. In addition, it is a further discovery of the present invention that many of the compounds or drugs that modulate (inhibit or enhance) alpha-4/beta-1 integrin binding also modulate alpha-9 integrin binding. This discovery therefore provides new pharmaceutical compositions and methods of treatment for modulating alpha-9 integrin binding, as well as screening methods for identifying new alpha-9 integrin modulatory compounds. SUMMARY OF THE INVENTION [0016] The invention is directed to pharmaceutical compositions and methods of treatment for disorders that involve binding of alpha-9 integrin, as well as screening assays that are useful in identifying compounds for use in such compositions and methods. More particularly, the invention is directed to inflammatory conditions, particularly those that involve increased adhesion macrophages or neutrophils, which, according to a discovery of the present invention, are now known to carry alpha-9 integrin in their membranes and to exhibit increased expression of alpha-9 integrin in response to stimulation by a known activator molecule, fMLP, as described herein. [0017] A number of inflammatory disorders are therefore susceptible to treatment in accordance with the present invention, including but not limited to airway hyper-responsiveness and occlusion that occur in conjunction with chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular occlusion following angioplasty, fibrosis and glomerular scarring as a result of renal disease, aortic stenosis, hypertrophy of synovial membranes in rheumatoid artritis, and inflammation and scarring that occur with the progression of ulcerative colitis, and Crohn's disease. [0018] In preferred embodiments, pharmaceutical compositions and methods of treatment of the invention employ alpha-9 antagonist compounds that inhibit binding between alpha-9 integrin and an alpha-9 integrin ligand. Preferred ligands in this regard include any ligand found to specifically bind to alpha-9 integrin, as exemplified by osteopontin, tenascin, and VCAM-1. Due to its association with inflammatory reactions, V-CAM-1 is particularly preferred for a test compound in this regard. [0019] In one embodiment, pharmaceutical compositions and treatment methods of the invention contain an alpha-9 integrin antagonist compound that exhibits a potency in inhibiting binding between alpha-9 integrin and an alpha-9 integrin ligand that is at least as high as {fraction (1/1000)}, and preferably at least as high as {fraction (1/100)} of an inhibitory potency exhibited by a compound selected from the group consisting of nine reference compounds: N-(toluene-4-sulfonyl)-L-prolyl-L- -4(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine, N-(toluene-4-sulfonyl)-L-prolyl-L-4(N,N-dimethylcarbamyloxy)phenylalanine- , N-(1-methylpyrazole-4-sulfonyl)-L-prolyl-L-4-(N,N-dimethylcarbamyloxy)ph- enylalanine, N-(toluene-4-sulfonyl)-L-(1,1-dioxo-5,5-dimethyl)thiaprolyl-L- -4-(N,N-dimethylcarbamyloxy)phenylalanine, N-(toluene-4-sulfonyl)-N-methyl- -L-alaninyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine, N-(toluene-4-sulfonyl)-L-[1,1-dioxo)thiamorpholin-3-carbonyl]-L-4-(N,N-di- methylcarbamyloxy)phenylalanine, N-(N-p-toluenesulfonyl)prolyl-4-(piperazi- noyloxy)phenylalanine, N-(N-p-toluenesulfonyl)sarcosyl-4-(N,N-dimethylcarb- amyloxy) phenylalanine, and N-(toluene-4-sulfonyl)-L-(5,5dimethyl)thiaprol- yl-L-4-[3-(N,N-dimethyl)propoxy]phenylalanine. [0020] The foregoing group of compounds are exemplary in nature, having been chosen for their relatively high potency in inhibiting alpha-9 integrin binding to an exemplary ligand, tenascin. The foregoing compounds also illustrate another aspect of the invention--that a rich source of candidate compounds for use in the pharmaceutical compositions and methods of treatment described herein is compounds known to inhibit binding or activity of alpha-4/beta-1 integrin (VLA-4). The foregoing 9 reference standard compounds can also be used in the pharmaceutical compositions and methods of treatment described above. Continue reading... Full patent description for Anti-inflammatory compositions and methods Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Anti-inflammatory compositions and methods patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. 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