MITOCHONDRIAL COMPOSITIONS AND USES THEREOF

• US 20100179106A1
• Filed: 09/08/2008
• Published: 07/15/2010
• Est. Priority Date: 09/07/2007
• Status: Abandoned Application

• Current Assignee: Gencia Corporation
• Original Assignee: Gencia Corporation
• Inventors: Khan, Shaharyar
• Application Number:
  US12/676,581
• Publication Number:
  US 20100179106A1
• Time in Patent Office: Days
• US Class Current: 514/77
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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
• CPC Class Codes: C07F 9/5022 Aromatic phosphines (P-C aromatic linkage)
• CPC Class Codes: C07F 9/5407 Acyclic saturated phosphonium compounds
• CPC Class Codes: C07F 9/5442 : Aromatic phosphonium compounds (P-C aromatic linkage)

Abstract

Compositions and methods for treating mitochondrial disorders are provided. The compositions include compounds having a mitochondrial targeting moiety, for example a lipophilic cation. Certain compounds are effective for increasing the ratio of phosphocreatine/creatine in a host, for example a mammal. Other compounds decrease the ratio of phophocreatine/creating in a host. An exemplary compound is defined by the following structure (Formula Ia): wherein R₁ is H or phosphate and the double bond is between N¹ and C¹ or between N² and C¹; R₂ is a mitochondrial targeting moiety; R₃ an alkyl, alkylaryl, alkylheteroaryl spacer group, a cleavable linker, or absent; R₄ is H or an alkyl, aryl, or heteroaryl group; and R₅ is alkyl, aryl, or heteroaryl; or N¹ C¹, and N together form a heterocyclic ring containing at least 5 atoms, wherein N¹, N³, and R₁-R₅ are as defined above, or N³ and R₅ together form a heterocyclic ring containing at least four atoms; or a pharmaceutically acceptable salt or prodrug thereof.

Claims

1. A compound having the following structure:

wherein R₁ is H or phosphate and the double bond is between N¹ and C¹ or between N² and C¹;

R₂ is a mitochondrial targeting moiety;

R₃ an alkyl, alkylaryl, alkylheteroaryl spacer group, a cleavable linker, or absent;

R₄ is H or an alkyl, aryl, or heteroaryl group; and

R₅ is alkyl, aryl, or heteroaryl;

or

N¹, C¹, and N³ together form a heterocyclic ring containing at least 5 atoms, wherein N¹, N³, and R₁-R₅ are as defined above, or

N³ and R₅ together form a heterocyclic ring containing at least four atoms;

or

a pharmaceutically acceptable salt or prodrug thereof.

2. The compound of claim 1 wherein the mitochondrial targeting moiety comprises a lipophilic cation.

3. The compound of claim 2 wherein the lipophilic cation comprises triphenylphosphonium.

4. The compound of claim 1 wherein the mitochondrial targeting moiety comprises polyarginine or polylysine.

5. The compound of claim 1 wherein the spacer group comprises a cleavable linkage.

6. The compound of claim 3 wherein the cleavable linkage is an ester linkage.

7. The compound of claim 1 having the following structure:

8. The compound of claim 1 having the following formula:

9. The compound of claim 1, wherein the compound is (triphenylphosphonio)methyl N-[amino(iminio)methyl]-N-methylglycinate or a pharmaceutically acceptable salt or prodrug thereof.

10. A pharmaceutical composition comprising the compound of anyone of claims 1-9 and a pharmaceutically acceptable excipient.

11. A method for increasing levels of phosphocreatine in a host comprising administering to the host the compound of any one of claims 1-9 or the pharmaceutical composition of claim 10.

12. A method for treating mitochondrial myopathy comprising

administering to a host having or suspected of having a mitochondrial myopathy the compound of any one of claims 1-10.

13. The method of claim 12 wherein the compound is administered in an amount effective to increase phosphocreatine levels in the host relative to a control.

14. The method of claim 13 wherein the increase in phosphocreatine levels occurs in mitochondria of the host.

15. The method of claim 12 wherein the mitochondrial myopathy is selected from the group consisting of Kearns-Sayre syndrome, Leigh'"'"'s syndrome, mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), myoclonus epilepsy with ragged red fibers (MERRF), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), neuropathy, ataxia and retinitis pigmentosa (NARP), and progressive external ophthalmoplegia (PEO).

16. A mitochondrial metabolite operably linked to a mitochondrial targeting moiety.

17. The mitochondrial metabolite of claim 16 wherein the mitochondrial targeting moiety is a lipophilic cation.

18. The mitochondrial metabolite of claim 17 wherein the lipophilic cation is a triphenylphosphonium ion.

19. The mitochondrial metabolite of claim 16 wherein the mitochondrial metabolite is selected from the group consisting of folate/folic acid, succinate, orotate, uridine, cytidine, pyruvate, vitamin A/retinoic acid, nicotinamide adenine dinucleotide (NAD+), NADH, nicotinamide adenine dinucleotide phosphate (NADP+), NADPH, ascorbic acid, folate, adenosine, adenosine diphosphate (ADP), adenosine triphosphate (ATP), adenosine monophosphate (AMP), glycerol, nonoate, s-adenosylemthionine (SAM), cyclic guano sine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), palmitate, acetyl-1-carnitine, alpha-lipoic acid, cardiolipin, cholesterol, acetyl-CoA, acetyl-CoA-SH, malohyl-CoA, glutamate, methylene blue, ascorbate, nitrite, alpha-ketoglutarate, acetate, acetaldehyde, lipoate, glutathione, glyceraldehyde 3-phosphate, malate, oxaloacetate, fumarate, ergocalciferol, cholecalciferol, biotin, valproate/valproic acid, phosphoenol pyruvate, glucose, glucose 6-phosphate, fructose, fructose-6-phosphate, fructose 1,6-bisphosphate, glycogen, UDP-glucose, glucose 1-phosphate, glutamine, glucosamine and analogs.

20. A method of treating a mitochondrial disorder comprising administering to a host an effective amount of the mitochondrial metabolite according to any one of claims 16-19 to alleviate one or more symptoms of the mitochondrial disorder.