Use of mitochondria-targeted electron scavengers as anti-inflammatory agents
View Patent ↗Provided herein are methods for using mitochondria-targeted electron scavengers as anti-inflammatory agents. The mitochondria-targeted electron scavenger comprises a free radical-scavenging group covalently linked to a mitochondria-targeting group derived from a hemigramicidin moiety. The mitochondria-targeted electron scavenger can be used to treat medical conditions associated with acute or chronic inflammation.
1. A method of inhibiting expression of nitric oxide, high mobility group protein B1, or inducible nitric oxide synthase comprising administering to a patient in need thereof a mitochondria-targeted electron scavenger chosen from one of
wherein R 1 is H or an acyl group, R 2 is H or an acyl group, and R is one of cyclopropane, -(E)-CH═CH—, and -(E)-CH═C(CH 3 ) or an isostere or stereoisomer thereof, or pharmaceutically acceptable salt of any of the above, and wherein X is a free radical scavenging group.
2. The method of claim 1 , wherein the mitochondria-targeted electron scavenger is acylated.
3. The method of claim 1 , wherein the patient is human.
4. The method of claim 1 , wherein the mitochondria-targeted electron scavenger is administered to the patient parenterally.
5. The method of claim 1 , wherein the mitochondria-targeted electron scavenger is administered to the patient orally.
6. The method of claim 1 , wherein the free radical-scavenging group comprises a nitroxide group.
7. The method of claim 6 , wherein the free radical-scavenging group comprises 2,2,6,6-tetramethylpiperidine-N-oxyl.
8. The method of claim 6 , wherein the free radical-scavenging group comprises 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl.
9. The method of claim 6 , wherein the free radical-scavenging group comprises 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl.
10. The method of claim 1 , wherein the mitochondria-targeted electron scavenger comprises a β-turn motif.
11. The method of claim 10 , wherein the β-turn motif comprises an alkene bond.
12. The method of claim 11 , wherein the alkene bond is an (E)-alkene bond.
13. The method of claim 10 , wherein the β-turn motif comprises a cyclopropane ring.
14. The method of claim 1 , wherein the mitochondria-targeted electron scavenger comprises one or more N-acylated amino acids.
15. The method of claim 14 , wherein the amino acid is acylated with one or more of the following acylating agents: aryloxycarbonyl agents, including benzyloxycarbonyl (Cbz) and fluorene-9-methyloxycarbonyl (FMOC) agents; and alkyloxycarbonyl agents, including tert-butoxycarbonyl (Boc), methoxycarbonyl, and trichloroethoxycarbonyl agents.
16. The method of claim 14 , wherein the N-acylated amino acid is N-Boc-Leu.
17. The method of claim 14 , wherein the N-acylated amino acid is Orn(Cbz).
18. The method of claim 1 , wherein the mitochondria-targeted electron scavenger comprises
wherein R 1 is H or an acyl group and R is the linkage between the Leu and D Phe residues and is one of cyclopropane, -(E)-CH═CH—, and -(E)-CH═C(CH 3 ) or an isostere or stereoisomer thereof, or pharmaceutically acceptable salt of any of the above.
19. The method of claim 18 , wherein the mitochondria-targeted electron scavenger is
20. The method of claim 1 , wherein the mitochondria-targeted electron scavenger comprises
wherein R 1 is an acyl group, R 2 is an acyl group, and R is the linkage between the Leu and D Phe residues and is one of cyclopropane, -(E)-CH═CH—, and -(E)-CH═C(CH 3 ).
21. The method of claim 20 , wherein the mitochondria-targeted electron scavenger is
22. The method of claim 1 , wherein the mitochondria-targeted electron scavenger comprises
or a pharmaceutically acceptable salt thereof.
23. The method of claim 1 , wherein the mitochondria-targeted electron scavenger comprises
or a pharmaceutically acceptable salt thereof.
24. The method of claim 1 , wherein an amount effective to inhibit expression of nitric oxide, high mobility group protein B1, or inducible nitric oxide synthase in the patient is from about 1 μmole/Kg per dose to about 100 μmoles/Kg per dose.
25. A method of inhibiting expression of nitric oxide, high mobility group protein B1, or inducible nitric oxide synthase comprising administering to a patient in need thereof a mitochondria-targeted electron scavenger chosen from one of
wherein R 1 is H or an acyl group, R 2 is H or an acyl group, and R is one of cyclopropane, -(E)-CH═CH—, and -(E)-CH═C(CH 3 )—, and —NH—C(═O)—; or an isostere or stereoisomer thereof, or pharmaceutically acceptable salt of any of the above, and wherein X is a free radical-scavenging group which contains a nitroxide moiety.
26. The method of claim 25 , the mitochondria-targeted electron scavenger having the structure
wherein R 1 is H or an acyl group and R 2 is H or an acyl group.