TIP60 inhibitors
This invention is in the fields of immunology and autoimmunity. More particularly it concerns pharmaceutical compositions comprising compounds which are useful agents for inhibiting the functions of TIP60 and the use of such compounds in the treatment of an individual suffering, for example, from ulcerative colitis and other irritable bowel diseases.
1. A pharmaceutical composition comprising a compound having a structure of Formula I:
wherein Ar 1 and Ar 2 are each independently phenyl, pyridinyl, naphthyl, or quinolinyl;
R 1 and R 3 are each independently at each occurrence alkyl, halo, hydroxyl, cyano, nitro, or alkoxy;
R 2 is H or alkyl; and m and n are independently 0, 1, or 2;
and at least one pharmaceutically acceptable carrier, diluent, excipient or auxiliary, said composition formulated in a unit dosage form suitable for oral administration, parenteral administration, rectal administration, topical administration, or vaginal administration to a mammal, wherein:
(a) the dosage form suitable for oral administration is a tablet capsule or lozenge;
(b) the dosage form suitable for parenteral administration comprises an aqueous solution selected from the group consisting of Hanks solution, Ringer's solution and a physiological saline buffer, and further optionally containing one or more emulsifying agents and/or suspending agents;
(c) the dosage form suitable for topical administration is a gel, lotion, cream, ointment foam, skin patch, wafers, or implant; and
(d) the dosage form suitable for rectal or vaginal administration is a suppository or pessary; and wherein the compound having a structure of Formula I is present in a therapeutically effective amount for treating multiple sclerosis, diabetes mellitus, rheumatoid arthritis, lupus, Crohn's disease, Hashimoto's disease, polymyositis, inflammatory bowel disease, colitis, scleroderma, oophoritis, thyroiditis, Grave's disease, dermatomyositis, Pemphigus vulgaris, myasthenia gravis, hemolytic anemia, or Sjogren's disease.
2. The pharmaceutical composition of claim 1 , wherein compound is present in the dosage form in an amount sufficient to inhibit HAT activity or expression.
3. The pharmaceutical composition of claim 1 , wherein Ar 1 is phenyl.
4. The pharmaceutical composition of claim 1 , wherein the compound has a structure of Formula II or Formula III:
where m and n are independently 1 or 2.
5. The pharmaceutical composition of claim 1 , wherein the compound has a structure of Formula IIA, IIIA, IVA, or IVB:
6. The pharmaceutical composition of claim 1 , wherein R 2 is H.
7. The pharmaceutical composition of claim 1 , wherein R 3 is independently halo at each occurrence.
8. The pharmaceutical composition of claim 1 , wherein R 3 is independently at each occurrence chloro or fluoro.
9. The pharmaceutical composition of claim 1 , wherein R 1 is independently at each occurrence C 1-3 alkyl, halo, or C 1-3 alkoxy.
10. The pharmaceutical composition of claim 1 , wherein R 1 is independently at each occurrence halo.
11. The pharmaceutical composition of claim 10 , wherein R 1 is independently at each occurrence chloro or fluoro.
12. The pharmaceutical composition of claim 10 , wherein R 3 is independently at each occurrence C 1-3 alkyl, halo, or C 1-3 alkoxy.
13. The pharmaceutical composition of claim 1 , wherein the compound has a structure of Formula B7, B7A, B7B, B7C, or B7G:
14. The pharmaceutical composition of claim 1 , wherein the composition is adapted in a dosage form suitable for oral administration, the dosage form being a tablet capsule or lozenge.
15. The pharmaceutical composition of claim 14 , wherein the composition is in the form of a tablet or capsule.
16. The pharmaceutical composition of claim 1 , wherein the formulation is in a dosage form suitable for parenteral administration, wherein said parenteral administration is selected from the group consisting of intratumor, intravenous, subcutaneous, intraperitoneal, and intramuscular administration.
17. The pharmaceutical composition of claim 15 , wherein the dosage form is a rolled or compressed tablet.
18. The pharmaceutical composition of claim 15 , wherein the dosage form is a liquid formulation contained within a soft or hard capsule.
19. The pharmaceutical composition of claim 17 , comprising one or more of:
(a) a carrier comprising calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, or a combination thereof;
(b) a disintegrant comprising sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, sodium alginate, or a combination thereof;
(c) a binder comprising microcrystalline cellulose, gelatin, sugar, polyethylene glycol, a natural or synthetic gum, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof;
(d) a diluent comprising lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dehydrate, or a combination thereof;
(e) a surface active agent comprising sodium lauryl sulfate, polysorbate 80, or a combination thereof;
(f) a glidant comprising silicon dioxide, talc, or a combination thereof;
(g) a lubricant comprising magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, or a combination thereof;
(h) a flavoring or taste-masking agent.
20. The pharmaceutical composition of claim 1 , wherein the dosage form is suitable for topical administration.
21. The pharmaceutical composition of claim 20 , wherein the dosage form is a gel, lotion, cream, ointment, or foam comprising an alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, or propylene glycol carrier.
22. The pharmaceutical composition of claim 1 , wherein the dosage form is a suppository or pessary.
23. The pharmaceutical composition of claim 1 , wherein the compound having a structure of Formula I is present in a therapeutically effective amount for treating Crohn's disease, inflammatory bowel disease, or colitis.
24. The composition of claim 17 wherein the pharmaceutically acceptable carrier is selected from the group consisting of calcium phosphate, magnesium stearate, talc, lactose, dextrin, starch, gelatin, cellulose, sodium carboxymethyl cellulose, and polyvinylpyrrolidine or a combination thereof.
25. The pharmaceutical composition of claim 17 , wherein: (a) the carrier is selected from the group consisting of calcium phosphate, magnesium stearate, talc, lactose, dextrin, starch, gelatin, cellulose, sodium carboxymethyl cellulose, and polyvinylpyrrolidine, or a combination thereof: (b) the diluent is selected from the group consisting of lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate, or a combination thereof: and (c) the excipient is selected from the group consisting of I-leucine, magnesium stearate, dextran, glucose, maltose, fructose, and trehalose.