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Compounds for enhancing hypoxia inducible factor activity and methods of use / Cornell Research Foundation, Inc.




Title: Compounds for enhancing hypoxia inducible factor activity and methods of use.
Abstract: The present invention relates to methods for enhancing Hypoxia inducible factor-1 (HIF) activity in a cell by contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide. ...


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USPTO Applicaton #: #20090215687
Inventors: Rajiv R. Ratan, Ambreena Siddiq, Juan C. Chavez


The Patent Description & Claims data below is from USPTO Patent Application 20090215687, Compounds for enhancing hypoxia inducible factor activity and methods of use.

The invention described in this application was made with funds from the National Institutes of Health, Grant Numbers NS 39170, NS 40591, and NS 46239. The United States Government has certain rights in this invention.

The invention was also made with funds from New York State, contract number CO19772. New York State has certain rights in this invention.

BACKGROUND

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OF THE INVENTION

Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional activator that regulates the expression of genes involved in adaptation to hypoxic stress. HIF-1 is composed of two subunits referred to as HIF-1α and HIF-1β. These subunits are expressly constitutively. During normal conditions, HIF-1α is targeted to ubiquitination and proteosomal degradation following hydroxylation of HIF-1 at proline 402 and 564 by the enzyme, prolyl hydroxylase.

Prolyl hydroxylases are reported to be oxygen-dependent. For example, under conditions of reduced oxygen, these enzymes function with low efficiency. As a result, HIF-1α is not hydroxylated, and thus not targeted to ubiquitination and degradation. Accordingly, HIF-1α becomes stabilized, and can bind HIF-1β to activate genes involved in adaptation to oxidative stress.

Oxidative stress is reported to be associated with numerous diseases and conditions, including stroke, hypoxia, ischemia, spinal cord injury and neurodegenerative conditions. Thus, compounds which enhance the activity of HIF-1α protein are beneficial for treating conditions and diseases associated with oxidative stress.

SUMMARY

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OF THE INVENTION

In one embodiment, the present invention relates to a method for enhancing HIF activity in a cell in need thereof. The method comprises contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide.

In another embodiment, the invention provides a method for treating a neurodegenerative disease or condition in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, ansindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

In yet another embodiment, the invention provides a method for treating hypoxia in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicine, aminopyridine, trimethoprim, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

In a further embodiment, the invention provides a method for treating stroke in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamime, anisindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine, colchicines, aminopyridine, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxalen, and hydralazine.

In yet a further embodiment, the invention provides a method for treating spinal cord injury in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, anisindione, nabumetone, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, deferoxamine mesylate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine.

In another embodiment, the invention provides a method for treating ischemia in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicine, aminopyridine, hydroxyurea, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Chemical structures of compounds.

FIG. 2. Amino acid sequence of HIFα protein, NCBI GenBank Accession No. Q16665.

FIG. 3. Tilorone analogues increase HIF-1 transcriptional activity.

FIG. 4. Tilorone analogues induce the expression of HIF-1 target genes in the rat cerebral cortex.

FIG. 5. A cell permeant, peptide inhibitor of the HIF prolyl 4-hydroxylase, but not a mutant control, induces expression of HIF-dependent genes. Tat-HIF/wt peptide (100 μM) but not a corresponding peptide with the C-terminal proline hydroxylation site of HIF-1α mutated (Tat-HIF/mut, 100 μM) significantly enhances the activity of a hypoxia response element driven reporter in cortical neurons (* corresponds to p<0.05 compared to control by paired T-test). The low molecular weight P4H inhibitor, FG-0041(40 μM) was used as a positive control.

FIG. 6. A cell permeant, peptide inhibitor of the HIF 4-hydroxylase, but not a mutant control, prevents oxidative glutamate toxicity. The glutamate analog, homocysteate (HCA) (5 mM) was added to cortical neurons (1 DIV) with or without Tat-HIF/wt peptide (30, 40, 50, 100 and 200 μM), Tat-HIF/mut peptide (200 μM), DFO (100 μM) and 3,4 DHB (10 μM). Twenty-four hours later cell viability was determined using the MTT assay. Graph depicts mean +/− SE for three experiments performed in triplicate (* denotes p<0.05 from HCA treated cultures by ANOVA and Student-Newman Keuls tests for control, Tat-HIF/wt, Tat-HIF/mut, DFO and 3,4 DHB).

DETAILED DESCRIPTION

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OF THE INVENTION Method for Enhancing HIF Activity

In another aspect, the invention provides a method for enhancing HIF activity in a cell in need thereof. The method comprises contacting the cell with an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIFalpha protein fused to a carrier peptide.

The HIF activity can be enhanced in any cell in need thereof. A cell in need of enhancing HIF activity includes cells that are, for example, suffering from trauma, injury, hypoxia, etc. Such cells include those discussed above.

The cell can be contacted with the compound by any method known to those in the art. For example, the cell can be contacted with the compound by incubating the cell and compound in vitro.

Alternatively, the cell can be contacted with the compound in vivo. The compound and cell can be contacted in vivo by any suitable method known to in the art, including the administration methods described below.

Method for Treating Neurodegenerative Disease or Condition

In one aspect, the invention provides a method for treating a neurodegenerative disease or condition in a mammal in need thereof. The method for treating a neurodegenerative disease or condition comprises administering to the mammal an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, ansindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

Neurodegenerative disease or condition typically refers to a disorder generally characterized by gradual and progressive loss of cells, tissue and/or organ of the central or peripheral nervous system. Examples of such cells, tissues and organs include, the brain, spinal cord, neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia.

Any mammal suffering from any neurodegenerative disease or condition can be treated in accordance with the method of the present invention. For example, the neurodegenerative disease or condition can be an acute condition. Acute conditions generally occur as a result of trauma to a cell, tissue and/or organ of the nervous system. The trauma can, for example, partially or completely block blood flow to the cell, tissue and/or organ. Examples of acute neurodegenerative conditions include head injury and brain injury.




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stats Patent Info
Application #
US 20090215687 A1
Publish Date
08/27/2009
Document #
File Date
12/31/1969
USPTO Class
Other USPTO Classes
International Class
/
Drawings
0


Albendazole Amiodarone Amiodarone Hydrochloride Atenolol Biochanin A Ciclopirox Citrate Clidinium Clidinium Bromide Clindamycin Clindamycin Hydrochloride Clofibrate Colchicine Daidzein Hydralazine Hydroxyurea Hydroxyzine Hypoxia Ibuprofen Lenin Mebendazole Monensin Mustine Nabumetone Nafcil Nafcillin Nafcillin Sodium Phenazo Phenazopyridine Pirenzepine Pramoxine Pramoxine Hydrochloride Profen Semustine Trimethoprim Trioxsalen Tripelennamine Citrate Triprolidine Hydrochloride Tropicamide Tryptophan Xylometazoline

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Cornell Research Foundation, Inc.


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Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai   Cyclopeptides   25 Or More Peptide Repeating Units In Known Peptide Chain Structure  

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20090827|20090215687|compounds for enhancing hypoxia inducible factor activity and methods of use|The present invention relates to methods for enhancing Hypoxia inducible factor-1 (HIF) activity in a cell by contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, |Cornell-Research-Foundation-Inc
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