Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-06-25
2001-05-08
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S224000
Reexamination Certificate
active
06228889
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention includes methods for treating conditions modulated by lactosylcerarnide and, more particularly, to the use of one or more compounds that inhibit UDP-galactose, GicCer, 1−>4 galactosyltransferase (GalT-2) to treat a subject suffering from or susceptible to a condition caused or contributed to by lactosylceramide. The present invention also relates to methods for detecting and analyzing compounds with therapeutic capacity to treat such conditions.
2. Background
Uncontrolled cell proliferation relates to conditions impacting the heart, kidney, liver and other organs. For example, uncontrolled cell proliferation is indicative of diseases such as certain vasculopathies, e.g., atherosclerosis, and pathologies involving neovascularization, tumor or cyst development, e.g., polycystic kidney disease and post-surgical keloid formation. In particular, uncontrolled proliferation of vascular cells can significantly contribute to disease by occluding blood flow and enhancing vessel remodeling. Certain post-surgical disorders such as restenosis are particularly affected by uncontrolled vascular cell proliferation. See generally
Harrison's Principles of Internal Medicine
, (1991) 12
th
ed. McGraw-Hill, Inc.; and Cole, B. R. (1990) in
The Cystic Kidney
, Dordrecht, Netherlands.
Invasive surgical procedures have been developed to alleviate certain diseases and post-surgical disorders. For example, certain surgical techniques involving angioplasty, and particularly balloon angioplasty, have been developed to enhance vascular flow. However, angioplast is often accompanied by side effects such as restenosis. In particular, restenosis is recognized as a serious post-surgical complication of angioplasty. See Landau, C., et al. (1994)
N. Eng. J. Med,
330:981 and references cited therein.
Further attempts to alleviate diseases and post-surgical disorders impacted by uncontrolled cell proliferation have employed certain therapeutic agents. For example, there has been much effort to develop agents that can reduce restenosis after angioplasty. More specifically, probucol is a recognized therapeutic agent that has been reported to reduce restenosis in some patients. However, existing probucol-based therapies are believed to be ineffective due to unsatisfactory patient tolerance and insufficient reduction of stenoses. See e.g., Tardif, J. C. et al., (1997)
N. Eng. J Med,
337:365-372; Ferns, G. A. A. et al. (1992)
PNAS
(USA) 89:11312 and references cited therein.
Efforts have been made to develop therapies that treat or prevent conditions affected by cell proliferation. For example, one approach has been to identify agents with therapeutic capacity to modulate cell pathways involving glycosphingolipids (GSLs). The GSLs are believed to impact lipid storage diseases, particularly glycosphingolipidoses and perhaps other lipid-related pathologies. See e.g., Chatterjee, S.,
Biochem. Biophys. Res Comm.
(1991) 181:554; Hakomori, S. I. (1983) in
Sphingolipid Chemistry
, eds. Kanfer, J. N. and Hakomori, S. I. (Plenum Press, New York) and references cited therein.
Certain biochemical steps relating to GlcCer and LacCer have been disclosed. For example, one step involves synthesis of GIcCer by coupling UDP-glucose to ceramide in a reaction catalyzed by UDP-glucose glucosyltransferase (GlcT-1). Another step converts the GicCer to LacCer using UDP-galactose, GicCer, &bgr;1−>4 galactosyltransferase (GalT-2). See eg., Chatterjee et al. supra
Attempts have been made to inhibit biochemical steps involving GlcT-1. For example, it has been reported that D-1-phenyl-2-decanolylamino-3-morpholino-1-propanol (D-PDMP) inhibits GlcT-1 and reduces proliferation of vascular cells. The mechanism of PDMP has been reported to be unclear. See e.g., Felding-Habermann, B., et al. (1991)
Biochemistry
29:6314; Shukla, G. S. et al.
Biochem. Biophys. Acta
(1991) 1083:101; Inokuchi, J. et al.,
J. Lipid Res.
(1987) 28:565; Chatterjee, S., supra.
Specified morpholinoceramides also have been disclosed as GlcT-1 inhibitors. See Carson, K. and B. Ganem (1994)
Tetrahedron Lets.
35:2659.
Other cell functions are believed to play a role in conditions modulated by LacCer. For example, uncontrolled cell adhesion is believed to effect specified immune responses such as allergic reactions and host rejection of foreign tissue.
It has been reported that uncontrolled cell proliferation and cell adhesion can affect certain vasculopathies. For example, atherosclerosis is believed to be worsened by adhesion of certain immune and vascular cells. Plaque formation is particularly enhanced by cell proteins such as intercellular adhesion molecule-1 (ICAM-1, CD54) and vascular cell adhesion molecule-1 (VCAM-1). See e.g., Kume, N. et al. (1992)
J. Clin. Invest.
90:1138; Iademarco, M. F. et al. (1995)
J. Clin. Invest.
95:264; Carlos, T. et al.
Blood
(1991) 77:2266; Nagel, T. et al. (1994)
J. Clin. Invest.
94:885; and Cybulsky, M. I. and Gimbrone M. A. (1991)
Science
251:788.
Certain GSLs also have been reported to be cell receptors for bacterial toxins. For example, cellular uptake of cholera toxin is believed to be enhanced by a membrane-associated GSLS.
Thus, it would be desirable to have additional methods of treating conditions or diseases modulated by lactosylceramides, e.g. to inhibit GalT-2, in order to treat or prevent such conditions.
SUMMARY OF THE INVENTION
We have now discovered therapies to treat or prevent various diseases, post-surgical disorders and bacterial infections modulated by lactosylceramide (LacCer). In particular, we have discovered therapies that include altering activity of UDP-galactose, GlcCer, &bgr;1−>4 galactosyl-transferase (GalT-2).
More specifically, the invention provides methods for treatment of proliferative disorders such as vasculopathies, e.g. atherosclerosis and restenosis; pathologies involving neovascularization; tumor or cyst development, e.g., polycystic kidney disease and post-surgical keloid formation; inflammatory diseases involving a proinflammatory cytokine such as TNF-&agr; or interleukin-6; and lipid storage diseases such as Gaucher's disease.
Therapies of the invention are particularly effective for the treatment and prevention of undesired vascular restenoses. In one protocol of the invention, a near absence of intimal proliferation was observed at the site of balloon angioplasty in the test subject (rabbit), whereas a control subject exhibited significant intimal proliferation. See the results set forth in the examples which follow.
LacCer-modulated diseases that can be treated in accordance with the invention also include lipid storage diseases (i.e. glycospingolipodoses) such as Gaucher's disease, cholesterol storage disease and the like.
Additional disorders that can be treated in accordance with the invention include bacterial infections, particularly those infections involving production of a toxin, such as an exotoxin that can specifically bind LaCer, e.g.
Neisseria gonorrhoeae
. See Paruchuri, D. K. et al. (1990)
Proc. Natl. Acad. Sci.
(USA), 87:333-337.
Therapeutic methods of the invention in general comprise administering to a subject, particularly a mammal such as a primate, especially a human, a therapeutically effective amount of a compound that can inhibit GalT-2 activity. Preferably, an administered compound inhibits cell proliferation by at least about 15% or 25% in a standard in vitro cell proliferation assay. Examples of such an assay are described below. It is generally preferred that the administered compound exhibits an IC
50
of at least about 500 &mgr;M in a standard in vitro GalT-2 assay as defined below, more preferably an IC
50
of about 100 &mgr;M or less, still more preferably an IC
50
of about 1-10 &mgr;M or less in a standard in vitro GalT-2 assay as defined below. Such compounds that can inhibit GalT-2 activity are generally referred to herein as “GalT-2 inhibitor compounds” or other similar term.
Compounds suitable for use in the trea
Buchanan Robert L.
Corless Peter F.
Higel Floyd D.
Johns Hopkins University
Sackey Ebenezer
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