Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1998-06-25
2001-10-16
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S529000, C514S784000, C514S785000, C514S824000, C514S825000, C514S903000, C530S387100, C562S400000
Reexamination Certificate
active
06303653
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutically effective compounds and methods of treating certain diseases/syndromes using such compounds.
REFERENCES
The following references are cited in the application as numbers in brackets or superscript at the relevant portion of the application.
1. Sladek, F. M., Zhong, W. M., Lai, E. Darnell, J. E., Jr. Gene Dev. 4, 2353-2365 (1990)
2. Sladek, F. M., in Liver Gene Expression (eds. Tronche, F. & Yaniv, M.) pp. 207-230, R. G. Landes Co., Austin, Tex. (1994)
3. The Metabolic and Inherited Bases of Inherited Disease (eds., Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D.) Vol. II, Part 8, 1995 (McGraw-Hill, Inc.)
4. Yamagata, K. et al., Nature 384, 4588-60 (1996)
5. DeFronzo, R. A. & Eleaterio, F. Diabetes Care 14, 173-194(1991)
6. Leff, T., Reue, K., Melian, A., Culver, H. & Breslow J. L. J. Biol. Chem. 264, 16132-16137 (1989)
7. Cave, W. T. FASEB J. 5,2160-2166 (1991)
8. Chin, J. P. F. Prost. Leuk. Essent. Fatty Acids 50, 211-222 (1994)
9. Grundy, S. M. & Denke, M. A. J. Lipid Res. 31, 1149-1172 (1990)
10. Storlien, L. H. et al., Science 237, 885-888 (1987)
11. Unger, R. H. Diabetes 44, 863-870 (1995)
12. Morris, M. C., Saks, F. & Rosner, B. Circulation 88, 523-533 (1993)
13. Hultin, M. B. Prog. Hemost. Thromb. 10, 215-241 (1991)
14. Bar-Tana, J., Rose-Kahn, G., Frenkel, B., Shafer, Z. & Fainaru, M. J. Lipid Res. 29, 431-441 (1988)
15. Tzur, R., Rose-Kahn, G., Adler, J. & Bar-Tana, J. Diabetes 37, 1618-1624 (1988)
16. Tzur, R., Smith, E. & Bar-Tana, J. Int. J. Obesity 13, 313-326 (1989)
17. Russel, J. C., Amy, R. M., Graham, S. E., Dolphin, P. J. & Bar-Tana, J. Arterioscler.
Thromb. Biol. 15, 918-923 (1995)
The disclosure of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if the language of each individual publication, patent and patent application were specifically and individually included herein.
BACKGROUND
Hepatocyte nuclear factor-4&agr;
1
(HNF-4, preferably HNF-4&agr;, (reviewed in ref. 2) is an orphan member of the superfamily of nuclear receptors. HNF-4&agr; is expressed in the adult and embryonic liver, kidney, intestine and pancreas and disruption of the murine HNF-4&agr; by homologous recombination results in embryo death. Like other members of the superfamily, the HNF-4&agr; receptor consists of a modular structure comprising a well conserved N-terminal DNA binding domain linked through a hinge region to a hydrophobic C-terminal ligand binding domain. Two HNF-4&agr; isoforms have been cloned and characterized: HNF-4&agr;1 and HNF-4&agr;2 comprising of a splice variant having a 10 amino acids insert in the C-terminal domain.
HNF-4&agr; is an activator of gene expression. Transcriptional activation by HNF-4&agr; is mediated by its binding as a homodimer to responsive DR-1 promoter sequences of target genes resulting in activation of the transcriptional initiation complex. Genes activated by HNF-4&agr; (reviewed in ref. 2) encode various enzymes and proteins involved in lipoproteins, cholesterol and triglycerides metabolism (apolipoproteins AI, AII, AIV, B, CIII, microsomal triglyceride transfer protein, cholesterol 7(hydroxylase), lipid metabolism (mitochondrial medium chain fatty acyl-CoA dehydrogenase, peroxisomal fatty acyl-CoA oxidase, cytochrome P-450 isozymes involved in fatty acyl &ohgr;-oxidation and steroid hydroxylation, fatty acid binding protein, cellular retinol binding protein II, transthyretin), glucose metabolism (phosphoenolpyruvate carboxykinase, pyruvate kinase, aldolase, glut2), amino acid metabolism (tyrosine amino transferase, ornitine transcarbamylase), blood coagulation (factors VII, IX, X), iron metabolism (transferrin, erythropoietin) and macrophage activation (hepatocyte growth factor-like protein/macrophage stimulating protein, Hepatitis B core and X proteins, long terminal repeat of human HIV-1, &agr;-1 antitrypsin).
Some genes activated by HNF-4&agr; play a dominant role in the onset and progression of atherogenesis, cancer, autoimmune and some other diseases
3
. Thus, overexpression of apolipoproteins B, AIV and CIII as well as of microsomal triglyceride transfer protein may result in dyslipoproteinemia (combined hypertriglyceridemia and hypercholesterolemia) due to increased production of very low density lipoproteins (VLDL) and chylomicrons combined with decrease in their plasma clearance. Similarly, enhanced pancreatic glycolytic rates leading to HNF-4&agr;/HNF-1-induced overexpression/oversecretion of pancreatic insulin may result in hyperinsulinemia leading to insulin resistance. Indeed, mutations in HNF-4&agr; and HNF-1 were recently shown to account for maturity onset diabetes of the young (MODY)
4
. Insulin resistance combined with HNF-4&agr;-induced overexpression of liver phosphoenolpyruvate carboxykinase and increased hepatic glucose production may result in impaired glucose tolerance (IGT) leading eventually to noninsulin dependent diabetes mellitus (NIDDM). Furthermore, hyperinsulinemia is realized today as major etiological factor in the onset and progression of essential hypertension and overexpression of HNF-4&agr; controlled genes may therefore further lead to hypertension. Furthermore, HNF-4&agr;-induced overexpression of blood coagulation factors combined perhaps with overexpression of inhibitors of blood fibrinolysis (e.g., plasminogen activator inhibitor-1) may lead to increased thrombus formation and decreased fibrinolysis with a concomitant aggravation of atherosclerotic prone processes.
Dyslipoproteinemia, obesity, IGT/NIDDM, hypertension and coagulation/fibrinolysis defects have been recently realized to be linked by a unifying Syndrome (Syndrome-X, Metabolic Syndrome, Syndrome of insulin resistance)
5
. High transcriptional activity of HNF-4&agr; resulting in overexpression of HNF-4&agr;-controlled genes may indeed account for the etiological linkage of Syndrome-X categories. Syndrome-X categories and the Syndrome in toto are realized today as major risk factors for atherosclerotic cardiovascular disease in Western societies, thus implicating HNF-4&agr; in initiating and promoting atherogenesis. Furthermore, since breast, colon and prostate cancers are initiated and promoted in Syndrome-X inflicted individuals, overexpression of HNF-4&agr; controlled genes could be implicated in the onset and progression of these malignancies.
In addition to the role played by HNF-4&agr; in the expression of Syndrome-X related genes, HNF-4&agr; activates the expression of genes which encode for proteins involved in modulating the course of autoimmune reactions. Thus, HNF-4&agr;-induced overexpression of the macrophage stimulating protein may result in sensitization of macrophages to self antigens or crossreacting antigens, thus initiating and exacerbating the course of autoimmune diseases, e.g., rheumatoid arthritis, multiple sclerosis and psoriasis. Furthermore, since transcription of hepatitis B core and X proteins as well as the long terminal repeat of human HIV-1 are controlled by HNF-4&agr;, HNF-4&agr; could be involved in modulating the course of infection initiated by these viral agents.
Since overexpression of HNF-4&agr;-induced genes may result in dyslipoproteinemia, IGT/NIDDM, hypertension, blood coagulability and fibrinolytic defects, atherogenesis, cancer, inflammatory, immunodeficiency and other diseases, inhibition of HNF-4&agr; transcriptional activity may be expected to result in amelioration of HNF-4&agr;-induced pathologies. However, no ligand has yet been identified for HNF-4&agr; which could serve as basis for designing inhibitors of HNF-4&agr; transcriptional activity. This invention is concerned with low molecular weight ligands of HNF-4&agr; designed to act as modulators of HNF-4&agr;-induced transcription and therefore as potential drugs in the treatment of pathologies induced by or involving HNF-4&agr;-controlled genes.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided therapeutically effective compounds comprisin
Geist Gary
Heller Ehrman White & McAuliffe LLP
White Everett
Yissum Research Development Company of The Hebrew University of
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