Methods of increasing proliferation of adult mammalian cardiomyocytes through p38 map kinase inhibition

• US 20060281791A1
• Filed: 04/28/2006
• Published: 12/14/2006
• Est. Priority Date: 04/29/2005
• Status: Abandoned Application

• Current Assignee: Children's Medical Center Corporation
• Original Assignee: Children's Medical Center Corporation
• Inventors: Keating, Mark T., Engel, Felix B.
• Application Number:
  US11/414,733
• Publication Number:
  US 20060281791A1
• Time in Patent Office: Days
• US Class Current: 514/355
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Compositions and methods for increasing proliferation and/or de-differentiation of postmitotic mammalian cardiomyocytes are disclosed to slow, reduce, or prevent the onset of cardiac damage. In addition, the methods and compositions of the invention can used to produce de-differentiated cardiomyocytes, which can then be used in tissue grafting, implantation or transplantation. The invention is based, in part, on the discovery that postmitotic mammalian cardiomyocytes can proliferate as a result of targeted disruption of p38 MAP kinase. p38 inhibition with optional growth factor stimulation can induce cytokinesis in adult cardiomyocytes.

Claims

1. Use of a compound comprising a p38 inhibitor or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for treatment of a condition or disease state to stimulate de-differentiation of post-mitotic cells.

2. The method of claim 1, wherein the post-mitotic cells are cardiomyocytes.

3. The method of claim 1 wherein the compound is selected from one or more of the classes of p38 inhibitors (A)-(I) described in the specification and pharmaceutically acceptable derivatives thereof.

4. The method of claim 1 wherein the compound is selected from 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(3,4-dimethylphenyl)methyl]-3-pyridinecarboxamide 1-oxide, and pharmaceutically acceptable derivatives thereof.

5. A method of inducing division of post mitotic cells, the method comprising

administering a p38 inhibitor or a pharmaceutically acceptable derivative thereof to a subject in an amount effective to stimulate de-differentiation of post-mitotic cells.

6. The method of claim 5, wherein the post-mitotic cells are cardiomyocytes.

7. The method of claim 5 wherein the p38 inhibitor or derivative thereof further comprises a compound selected from the group of formula (A)-(I) described in the specification, and pharmaceutically acceptable derivatives thereof.

8. The method of claim 5 wherein the p38 inhibitor or derivative thereof further comprises a compound selected from the group of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-trimethylpropyl)]-3-pyridinecarboxamide 1-oxide;

6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(3,4-dimethylphenyl)methyl]-3-pyridinecarboxamide 1-oxide, and pharmaceutically acceptable derivatives thereof.

9. The method of claim 5, wherein the step of administering an effective amount of p38 inhibitors is selected from the group comprising oral administration, intravenous injection, topical administration, and myocardial injection.

10. The method of claim 5, wherein the step of administration comprises implanting a stent in the subject, such that the stent is capable of delivering p38 inhibitors to the subject'"'"'s organ.

11. The method of claim 5, where the method upregulates cyclin A2.

12. A method of repairing heart tissue, the method comprising

identifying a subject in need of heart tissue repair, and

administering to the subject an effective amount of p38 inhibitor, such that proliferation of cardiomyocytes increases.

13. The method of claim 12, wherein the subject underwent myocardial ischemia, hypoxia, stroke, or myocardial infarction.

14. The method of claim 13, wherein the method further comprises administering an effective amount of FGF1, wherein the p38 inhibitor and FGF1 act synergistically to induce proliferation of cardiomyocytes.

15. The method of claim 13, wherein the method downregulates antagonists of PI3 kinase.

16. The method of claim 13, wherein the antagonist of PI3 kinase is Seta/Ruk.

17. A method for producing de-differentiated of cardiomyocytes comprising the steps of:

selecting terminally differentiated cells from a tissue that includes said cells;

resuspending said concentrated cells in a growth medium containing an effective amount of p38 inhibitor; and

culturing said resuspended cells in the growth medium for a time and under conditions to effect de-differentiation of at least a portion of said selected cells in culture,

wherein at least a portion of said selected terminally differentiated cells in culture undergo at least one round of cardiomyocyte division.

18. The method of claim 17, wherein the growth medium comprises FGF1.