Compositions and methods relating to salts of specialized pro-resolving mediators
The present invention relates to compounds of Formula IV, compositions comprising same, and their use in therapy wherein A and B are each independently a specialized pro-resolving mediator (“SPM”) molecule selected from an E series resolvin, a D series resolvin, and their aspirin-triggered counterparts, and M, R 1 , R 2 , X 1 and X 2 are as defined herein.
1. A compound of Formula IV which contains a scaffold of two amino acid moieties coordinated around a divalent metal and one or two SPM molecules A, B, ionically bound to at least one basic function provided by the scaffold:
wherein
M is a divalent metal selected from magnesium (Mg 2+ ) and calcium (Ca 2+ ),
A and B are each independently an SPM molecule selected from an E series resolvin, a D series resolvin, and their aspirin-triggered counterparts,
A and B may be the same or different,
either A or B, but not both, may be absent,
R 1 and R 2 are each independently —(CH 2 ) 3 —Y 1 , and —(CH 2 ) 4 —Y 2 ,
where Y 1 and Y 2 are each a basic function selected from a positively charged primary amine, a positively charged secondary amine, a positively charged tertiary amine, and a positively charged guanidine,
X 1 and X 2 are each independently H or CO—Z and Z is a peptide comprising 1 to 5 amino acids.
2. The compound of claim 1 , wherein M is magnesium (Mg 2+ ).
3. The compound of claim 2 , wherein X 1 and X 2 are each H.
4. The compound of claim 3 , wherein R 1 and R 2 are each —(CH 2 ) 4 —Y 2 and Y 2 is —NH 3+ .
5. The compound of claim 4 , wherein A and B are each independently an E series resolvin selected from the group consisting of resolvin E1 (RvE1), resolvin E2 (RvE2), resolvin E3 (RvE3), aspirin-triggered RvE1 (AT-RvE1), AT-RvE2, and AT-RvE3 or a D series resolvin selected from the group consisting of resolvin D1, resolvin D2, resolvin D3, resolvin D4, resolvin D5, and D6, and their aspirin-triggered counterparts.
6. The compound of claim 5 , wherein A and B are both present and A and B are the same.
7. The compound of claim 6 , wherein A and B are selected from the group consisting of RvE1, AT-RvE1, RvE2, and RvE3.
8. The compound of claim 6 , wherein A and B are selected from RvE1 or AT-RvE1.
9. The compound of claim 1 , which is selected from the group consisting of RvE1-MgLys, RvE1-CaLys, AT(18S)-RvE1-MgLys, AT(18S)-RvE1-CaLys, RvE2-MgLys, RvE2-CaLys, AT-RvE2-MgLys, AT-RvE2-CaLys, RvE3-MgLys, RvE3-CaLys, AT-RvE3-MgLys and AT-RvE3-CaLys of Table 5.
10. The compound of claim 1 , which is selected from the group consisting of RvE1-MgLys, RvE1-CaLys, AT(18S)-RvE1-MgLys and AT(18S)-RvE1-CaLys of Table 5.
11. A pharmaceutical composition comprising the compound of claim 1 , and a carrier or excipient.
12. A pharmaceutical composition comprising the compound of claim 6 , and a carrier or excipient.
13. A method for treating inflammation in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1 .
14. A method for treating a disease or disorder selected from ulcerative colitis, Crohn's disease, proctitis, pouchitis, Crohn's disease of the pouch, eosinophilic colitis, lymphocytic colitis, collagenous colitis, diversion colitis, chemical colitis, and ischemic colitis in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1 .
15. The method of claim 14 , wherein the disease or disorder is selected from ulcerative colitis, Crohn's disease, and pouchitis.
16. A method for treating a gastrointestinal disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1 , wherein the gastrointestinal disease or disorder is selected from eosinophilic esophagitis, Behcet's disease, irritable bowel syndrome, Celiac disease, intestinal mucositis, diverticulitis, and short bowel syndrome.
17. A method of making the compound of claim 1 , the method comprising contacting a solution of the SPM in a nonaqueous solvent with an amount of magnesium or calcium di-lysinate, such that the molar amount of the SPM to the metal di-lysinate is 2:1.
18. The method of claim 17 , wherein the solution further comprises an antioxidant.
19. A method for treating an inflammatory disease or disorder in a subject in need thereof, the inflammatory disease or disorder selected from asthma, ischemia reperfusion injury, lyme arthritis, periodontitis, peritonitis, psoriasis, rheumatoid arthritis, scleroderma, oral mucositis, stomatitis, chelitis, glossitis, Sjogren's syndrome and systemic inflammatory response syndrome, the method comprising administering to the subject an effective amount of the compound of claim 1 .
20. The method of claim 19 , wherein the inflammatory disease or disorder is oral mucositis.
21. The method of claim 20 , wherein the method comprises administering to the subject an effective amount of the compound wherein
M is magnesium (Mg 2+ ),
X 1 and X 2 are each H,
R 1 and R 2 are each —(CH 2 ) 4 —Y 2 and Y 2 is —NH 3+ ,
A and B are both present and are the same, and
A and B are selected from RvE1 or AT-RvE1.
22. The method of claim 21 , wherein A and B are RvE1.