P38 map kinase inhibitors for treating Friedreich's ataxia

Patent metadata

Field	Value
Publication number	US-12370180-B2
Application number	US-201615561390-A
Country	US
Kind code	B2
Filing date	Mar 23, 2016
Priority date	Mar 24, 2015
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

The invention provides p38 MAPK inhibitors that compensate for a frataxin deficiency or mutation and methods of using the same (e.g., to treat Friedreich's ataxia).

First claim

What is claimed is:

1. A method for treating a subject at risk for developing Friedreich's ataxia or suffering from Friedreich's ataxia or reducing the symptoms thereof comprising administering to the subject a therapeutically effective amount of a p38 mitogen-activated protein kinase (MAPK) inhibitor or a pharmaceutical composition thereof, wherein the p38 MAPK inhibitor is selected from the group consisting of ARRY-371797, ARRY-614 (pexmetinib), AZD-7624, LY-2228820 (ralimetinib dimesylate), LY-3007113, FX005, GSK610677, GW856553 (losmapimod), SB-681323 (dilmapimod), KC706, UR-13870, PF-03715455, VX-745, SCIO-469 (talmapimod), PH-797804, VX-702, SB-202190 (FHPI), SB-239063, BIRB-796 (doramapimod), BMS-582949, pamapimod, and pharmaceutically acceptable derivatives thereof.

2. The method according to claim 1 , wherein the inhibitor is administered in combination with one or more additional p38 MAPK inhibitors.

3. The method according to claim 1 , wherein the subject is a human.

4. The method according to claim 1 , further comprising the step of administering an additional agent for treating the subject.

5. A method for compensating for a frataxin deficiency or mutation in a subject comprising administering to the subject a therapeutically effective amount of a p38 mitogen-activated protein kinase (MAPK) inhibitor or a pharmaceutical composition thereof, wherein the p38 MAPK inhibitor is selected from the group consisting of ARRY-371797, ARRY-614 (pexmetinib), AZD-7624, LY-2228820 (ralimetinib dimesylate), LY-3007113, FX005, GSK610677, GW856553 (losmapimod), SB-681323 (dilmapimod), KC706, UR-13870, PF-03715455, VX-745, SCIO-469 (talmapimod), PH-797804, VX-702, SB-202190 (FHPI), SB-239063, BIRB-796 (doramapimod), BMS-582949, pamapimod, and pharmaceutically acceptable derivatives thereof.

6. The method according to claim 5 , wherein the inhibitor is administered in combination with one or more additional p38 MAPK inhibitors.

7. The method according to claim 5 , wherein the subject is a human.

8. The method according to claim 5 , further comprising the step of administering an additional agent for treating the subject.

9. A method for compensating for a frataxin deficiency or mutation in a primary fibroblast cell comprising administering to the primary fibroblast cell an effective amount of a p38 mitogen-activated protein kinase (MAPK) inhibitor, wherein the p38 MAPK inhibitor is selected from the group consisting of ARRY-371797, ARRY-614 (pexmetinib), AZD-7624, LY-2228820 (ralimetinib dimesylate), LY-3007113, FX005, GSK610677, GW856553 (losmapimod), SB-681323 (dilmapimod), KC706, UR-13870, PF-03715455, VX-745, SCIO-469 (talmapimod), PH-797804, VX-702, SB-202190 (FHPI), SB-239063, BIRB-796 (doramapimod), BMS-582949, pamapimod, and pharmaceutically acceptable derivatives thereof.

10. The method according to claim 9 , wherein administering to the cell comprises administering to the cell in vitro, in vivo, or ex vivo.

11. The method according to claim 1 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or diluent, a binder, or a preservative.

12. The method according to claim 5 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or diluent, a binder, or a preservative.

13. A method for increasing frataxin gene expression or a phenotype thereof in a cell having a frataxin deficiency or mutation, the method comprising administering to the cell an effective amount of a p38 mitogen-activated protein kinase (MAPK) inhibitor or a pharmaceutically acceptable derivative thereof, wherein the p38 MAPK inhibitor is selected from the group consisting of ARRY-371797, ARRY-614 (pexmetinib), AZD-7624, LY-2228820 (ralimetinib dimesylate), LY-3007113, FX005, GSK610677, GW856553 (losmapimod), SB-681323 (dilmapimod), KC706, UR-13870, PF-03715455, VX-745, SCIO-469 (talmapimod), PH-797804, VX-702, SB-202190 (FHPI), SB-239063, BIRB-796 (doramapimod), BMS-582949, pamapimod, and pharmaceutically acceptable derivatives thereof.

14. The method according to claim 13 , further comprising decreasing the level of oxidative stress, decreasing the level of mitochondrial iron, and/or increasing the level of mitochondrial production of adenosine triphosphate (ATP) in the cell.

15. The method according to claim 13 , wherein administering to the cell comprises administering to the cell in vitro, in vivo, or ex vivo.

16. A method for altering cytokine expression or secretion in a cell having a frataxin deficiency or mutation, the method comprising administering to the cell an effective amount of a p38 mitogen-activated protein kinase (MAPK) inhibitor or a pharmaceutically acceptable derivative thereof, wherein the p38 MAPK inhibitor is selected from the group consisting of ARRY-371797, ARRY-614 (pexmetinib), AZD-7624, LY-2228820 (ralimetinib dimesylate), LY-3007113, FX005, GSK610677, GW856553 (losmapimod), SB-681323 (dilmapimod), KC706, UR-13870, PF-03715455, VX-745, SCIO-469 (talmapimod), PH-797804, VX-702, SB-202190 (FHPI), SB-239063, BIRB-796 (doramapimod), BMS-582949, pamapimod, and pharmaceutically acceptable derivatives thereof.

17. The method according to claim 16 , further comprising decreasing cytokine expression or secretion, wherein the cytokine is in the group consisting of IL6 (IL-6), IL8 (IL-8), GM-CSF, RANTES, IL1-beta (IL-1-beta), VEGF, MCP-1, IP10 (IP-10), and GRO.

18. The method according to claim 16 , wherein administering to the cell comprises administering to the cell in vitro, in vivo, or ex vivo.

Assignees

• The Trustees Of The Univ Of Pennyslvania
• Univ Pennsylvania

Inventors

• Wilson Robert B
• Cotticell Maria Grazia
• Wang Yongping
• Xia Shujuan
• Kaur Avinash
• Tobias John W

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/4418

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine · CPC title