LDH INHIBITORS AS TREATMENT FOR FIBROSIS AND FIBROTIC-RELATED DISORDERS

• US 20150335674A1
• Filed: 05/21/2015
• Published: 11/26/2015
• Est. Priority Date: 05/21/2014
• Status: Active Grant

• Current Assignee: University of Rochester
• Original Assignee: University of Rochester
• Inventors: Phipps, Richard P., Kottmann, Robert M., Sime, Patricia J.
• Granted Patent: US 9,750,761 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 31/12 Ketones
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: C12Y 101/01027 L-Lactate dehydrogenase (1.1.1.27)
• CPC Class Codes: C12Y 101/01028 D-Lactate dehydrogenase (1.1.1.28)

Abstract

One aspect of the disclosure relates to methods of treating a fibrotic condition in an individual. The methods include administering to an individual having a fibrotic condition an effective amount of a lactic dehydrogenase (LDH) inhibitor, wherein the fibrotic condition involves an internal organ or tissue, or ocular tissue, and said administering is effective to treat the fibrotic condition. Methods of administration and pharmaceutical compositions and systems for practicing such methods are also disclosed.

Claims

1. A method of treating a fibrotic condition in an individual, said method comprising:

administering to an individual having a fibrotic condition an effect amount of a lactic dehydrogenase (LDH) inhibitor, wherein the fibrotic condition involves an internal organ or tissue, or ocular tissue, and said administering is effective to treat the fibrotic condition.

2. The method according to claim 1, wherein the fibrotic condition is not a cancerous proliferative disorder, idiopathic arthrofibrosis, or dermatological scarring.

3. The method according to claim 2, wherein the method consists of said administering.

4. The method according to claim 1, wherein the method excludes administration of a cancer therapy.

5. The method according to claim 1, wherein the LDH inhibitor is an LDH5 inhibitor.

6. The method according to claim 1, wherein the LDH inhibitor is an RNAi specific for LDH, oxamate, gossypol, galloflavin, 3-hydroxyisoxazole-4-carboxylic acid (HICA), 4-hydroxy-1,2,5-thiadiazole-3-carboxylic acid (HTCA), a derivative of 8-deoxyhemigossylic (2,3-dihydroxynaphtalen-1-carboxylic) acid, an N-hydroxyindole-based inhibitor designated FX11, or elesclomol.

7. The method according to claim 1, wherein the LDH inhibitor is a compound according to formula (I):

8. The method of claim 1, wherein said internal organ comprises lung, liver, kidney, heart, pancreas, gastrointestinal organs, or genitourinary organs.

9. The method of claim 1, wherein said internal tissue comprises vascular tissue.

10. The method of claim 1, wherein said ocular tissue comprises corneal tissue or retinal tissue.

11. The method of claim 1, wherein the fibrosis is pulmonary fibrosis.

12. The method of claim 1, wherein said administering is effective to inhibit one or more of TGF-β

-induced myofibroblast differentiation, pro-fibrotic gene expression, lactic acid production that reduces extracellular pH, and progression of the fibrosis.

13. The method of claim 1, wherein said administering is carried out orally, parenterally, periadventitially, subcutaneously, intravenously, intramuscularly, intraperitoneally, by inhalation, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, intradermally or by application to mucous membranes.

14. The method according to claim 1, further comprising administering at least one additional anti-fibrotic agent to the individual.

15. The method according to claim 14, wherein said additional anti-fibrotic agent is selected from the group consisting of calcium channel blockers, cytotoxic agents, cytokines, chemokines, integrins, growth factors, hormones, lysophosphatidic acid (LPA) receptor 1 antagonists, agents that modulate the TGF-β

pathway, endothelin receptor antagonists, agents that reduce connective tissue growth factor (CTGF) activity, matrix metalloproteinase (MMP) inhibitors, agents that reduce the activity of platelet-derived growth factor (PDGF), agents that interfere with integrin function, agents that interfere with the pro-fibrotic activities of cytokines, agents that reduce oxidative stress, PDE4 inhibitors, PDE5 inhibitors, mTor inhibitors, modifiers of the arachidonic acid pathway, peroxisome proliferator-activated receptor (PPAR)-γ

agonists, kinase inhibitors, inhibitors of VEGF signaling pathway, matrix metalloproteinases, tissue inhibitors of metalloproteinases (TIMPs), HGF agonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, inhibitors of advanced glycation endproducts (AGEs) or their receptors (RAGEs), Rho kinase inhibitors, PKC inhibitors, ADAM-10 inhibitor, farnesoid X receptor agonists, caspase inhibitors, anti-oxidants, inhibitors of collagen expression, LMW heparin or heparin analogs, copper chelators, TNF-α

blocking agents, HMG-CoA reductase inhibitors, and Thy-1 (CD90) inhibitors.

16. The method according to claim 14, wherein said administering of the at least one additional anti-fibrotic agent is carried out orally, parenterally, periadventitially, subcutaneously, intravenously, intramuscularly, intraperitoneally, by inhalation, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, intradermally or by application to mucous membranes.

17. A pharmaceutical composition or system comprising therapeutically effective amounts of a lactic dehydrogenase (LDH) inhibitor and at least one additional anti-fibrotic agent, each in a pharmaceutically acceptable carrier.

18. The pharmaceutical composition or system according to claim 17, wherein the LDH inhibitor is an RNAi specific for LDH, oxamate, gossypol, galloflavin, 3-hydroxyisoxazole-4-carboxylic acid (HICA), 4-hydroxy-1,2,5-thiadiazole-3-carboxylic acid (HTCA), a derivative of 8-deoxyhemigossylic (2,3-dihydroxynaphtalen-1-carboxylic) acid, an N-hydroxyindole-based inhibitor designated FX11, or elesclomol.

19. The pharmaceutical composition or system according to claim 17, wherein the LDH inhibitor is a compound according to formula (I):

20. The pharmaceutical composition or system according to claim 17, wherein said additional anti-fibrotic agent is selected from the group consisting of calcium channel blockers, cytotoxic agents, cytokines, chemokines, integrins, growth factors, hormones, lysophosphatidic acid (LPA) receptor 1 antagonists, agents that modulate the TGF-β

pathway, endothelin receptor antagonists, agents that reduce connective tissue growth factor (CTGF) activity, matrix metalloproteinase (MMP) inhibitors, agents that reduce the activity of platelet-derived growth factor (PDGF), agents that interfere with integrin function, agents that interfere with the pro-fibrotic activities of cytokines, agents that reduce oxidative stress, PDE4 inhibitors, PDE5 inhibitors, mTor inhibitors, modifiers of the arachidonic acid pathway, peroxisome proliferator-activated receptor (PPAR)-γ

agonists, kinase inhibitors, inhibitors of VEGF signaling pathway, matrix metalloproteinases, tissue inhibitors of metalloproteinases (TIMPs), HGF agonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, inhibitors of advanced glycation endproducts (AGEs) or their receptors (RAGEs), Rho kinase inhibitors, PKC inhibitors, ADAM-10 inhibitor, farnesoid X receptor agonists, caspase inhibitors, anti-oxidants, inhibitors of collagen expression, LMW heparin or heparin analogs, copper chelators, TNF-α

blocking agents, HMG-CoA reductase inhibitors, and Thy-1 (CD90) inhibitors.

21. The pharmaceutical composition or system according to claim 17, wherein the LDH inhibitor and the additional anti-fibrotic agent are present together in a single composition with the pharmaceutically acceptable carrier.