Selective targeting agents for mitochondria

• US 7,528,174 B2
• Filed: 08/17/2006
• Issued: 05/05/2009
• Est. Priority Date: 01/06/2006
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Wipf, Peter, Xiao, Jingbo, Fink, Mitchell P., Kagan, Valerian E., Tyurina, Yulia Y.
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): BRADLEY, CHRISTINA
• Application Number:
  US11/465,162
• Publication Number:
  US 20070161573A1
• Time in Patent Office: 992 Days
• Field of Search: None
• US Class Current: 514/645
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65

Abstract

Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using specific structural signaling features recognizable by cells as mitochondrial targeting sequences are discussed. A method for delivering these agents effectively into cells and mitochondria where they act as electron scavengers by way of certain targeting sequences is also disclosed. Mitochondria dysfunction and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient. In a preferred embodiment, the compositions and methods may be administered therapeutically in the field to patients with profound hemorrhagic shock so that survival could be prolonged until it is feasible to obtain surgical control of the bleeding vessels.

Claims

1. A compound selected from the group consisting of:

2. The compound of claim 1, having the structure:

3. The compound of claim 1, having the structure:

4. The compound of claim 1, having the structure:

5. The compound of claim 1, having the structure:

15. A method for making the compound of claim 1, comprising:

a. Hydrozirconating an alkyne

16. The method of claim 15, further coupling the third intermediate with 4-amino-TEMPO to produce

17. The method of claim 15, further comprising:

a. Coupling a tripeptide H-Pro-Val-Orn(Cbz)-OMe to the third intermediate using a coupling agent yielding a fourth intermediate;

6. A compound for scavenging radicals in a mitochondrial membrane comprising a free radical scavenging group covalently linked to a membrane-targeting peptidyl fragment, the compound having the structure:

7. A method for delivering TEMPO to mitochondria comprising contacting the mitochondria with a compound selected from the group consisting of:

8. The method of claim 7, comprising delivering the compound to the mitochondria in an amount sufficient to scavenge reactive oxygen species.

9. The method of claim 7, wherein the compound is:

10. The method of claim 7, wherein the compound is:

11. A method for therapeutically treating a patient having a condition associated with or caused by reactive oxygen species exposure comprising administering to said patient a compound selected from the group consisting of:

12. The method of claim 11, wherein said patient is a human being.

13. The method of claim 11, wherein said condition is hemorrhagic shock.

14. The method of claim 11, wherein said condition is selected from the group consisting of myocardial ischemia, myocardial reperfusion, solid organ transplantation, hemorrhagic shock, septic shock, stroke, tissue damage due to ionizing radiation, lung injury, acute lung injury, acute respiratory distress syndrome, necrotizing pancreatitis, and necrotizing enterocolitis.