TREATMENT OF MITOCHONDRIAL DISORDERS USING A FARNESYL TRANSFERASE INHIBITOR

• US 20110060005A1
• Filed: 04/07/2010
• Published: 03/10/2011
• Est. Priority Date: 11/13/2008
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Link Medicine Corp. (Astrazeneca PLC)
• Inventors: LIU, ZHIHUA, JUSTMAN, CRAIG J., LYNCH, BERKLEY A., LANSBURY, PETER T. JR., GRAMMATOPOULOS, TOM N.
• Application Number:
  US12/756,052
• Publication Number:
  US 20110060005A1
• Time in Patent Office: Days
• US Class Current: 514/312
• 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 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4406 only substituted in position 3, e.g. zimeldine nicotinic acid A61K31/455
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Methods and pharmaceutical compositions comprising a low dose of a farnesyl transferase inhibitor useful in the treatment of proteinopathies and mitochondrial disorders are provided. These low doses are below the doses used in oncological treatments for which these compounds were initially designed. The treatment includes administering to a subject an amount of a farnesyl transferase inhibitor, wherein the amount administered is sufficient to stimulate mitophagy in said subject. Treatments in accordance with the present invention may also include an acetylcholinesterase inhibitor, an activator of neurotrophic receptors, an NMDA anatagonist, an amyloid deposit inhibitor, an antipsychotic agent, an antidepressant, an anxiolytic, or an antioxidant.

Claims

1. A method of treating a proteinopathic subject or a subject with a mitochondrial disorder, wherein the method comprises administering a compound selected from:

2. The method of claim 1, wherein said compound increases autophagic flux in said subject, which results in improved mitochondrial health.

3. The method of claim 1, wherein the subject is suffering from a mitochondrial disorder, wherein decreased mitochondrial function is responsible, wholly or in part, for the symptoms of said disease.

4. The method of claim 3, wherein the disease that the subject is suffering from is selected from MELAS, Leber syndrome, type 2 diabetes, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Crohn'"'"'s disease, and mitochondrial myopathies, progressive supranuclear palsy (PSP), Lewy Body Disease (LBD), ALS (amyotophic lateral sclerosis/Lou Gehrig'"'"'s disease), and Huntington'"'"'s disease.

5. The method of claim 1, wherein said compound provides at least one of the following:

(i) prevents cell death from glucolipotoxicity;

(ii) protects cells from glucolipotoxicity-induced fragmentation;

(iii) increases insulin secretion by cells under glucose stimulated conditions;

(iv) does not increase insulin secretion by cells under basal glucose conditions;

or

(v) increases oxygen consumption of cells.

6. The method according to claim 1, wherein said compound acts on a single mitochondria.

7. The method according to claim 1, wherein the amount said compound or a pharmaceutically acceptable salt thereof, administered ranges from approximately 0.1 mg per day to approximately 50 mg per day.

8. The method according to claim 1, wherein the amount of said compound or a pharmaceutically acceptable salt thereof, is not sufficient to inhibit the farnesylation of Ras in the brain by more than about 50%.

9. The method according to claim 1, wherein the amount of said compound or a pharmaceutically acceptable salt thereof, is sufficient to inhibit the farnesylation of UCH-L1.

10. The method according to claim 1, wherein the pharmaceutically acceptable salt administered is the D-tartrate salt of

11. The method according to claim 1, wherein the proteinopathic subject is suffering from a neurodegerative disease, a cognitive impairment, a lysosomal storage disease, an ocular disease, an inflammatory disease, a cardiovascular disease, or a proliferative disease.

12. The method according to claim 11, wherein the neurodegenerative disease is selected from Parkinson'"'"'s disease, diffuse Lewy body disease, multiple system atrophy, pantothenate kinase-associate neurodegeneration, amyotrophic lateral sclerosis, Huntington'"'"'s disease, and Alzheimer'"'"'s disease.

13. The method according to claim 1, further comprising administering to the subject a therapeutically effective amount of a non-farnesyl transferase inhibitor.

14. The method according to claim 13, wherein the non-farnesyl transferase inhibitor is selected from the group consisting of dopamine agonists, DOPA decarboxylase inhibitors, dopamine precursors, monoamine oxidase blockers, cathechol O-methyl transferase inhibitors, anticholinergics, acetylcholinesterase inhibitors, activators of neurotrophic receptors, gamma-secretase inhibitors, PDE10 inhibitors, and NMDA antagonists.

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

16. A pharmaceutical composition for treating a proteinopathic subject or a subject with a mitochondrial disorder, comprising a compound selected from

17. The pharmaceutical composition according to claim 16 comprising approximately 0.1 mg per day to approximately 50 mg per day of the compound or pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 16, wherein the pharmaceutically acceptable salt is the D-tartrate salt of

19. The pharmaceutical composition according to claim 16, wherein the proteinopathic subject is suffering from a neurodegerative disease, a cognitive impairment, a lysosomal storage disease, an ocular disease, an inflammatory disease, a cardiovascular disease, and a proliferative disease.

20. The pharmaceutical composition according to claim 19, wherein the neurodegenerative disease is selected from Parkinson'"'"'s disease, diffuse Lewy body disease, multiple system atrophy, pantothenate kinase-associate neurodegeneration, amyotrophic lateral sclerosis, Huntington'"'"'s disease, and Alzheimer'"'"'s disease.