COMPOSITIONS AND METHODS FOR TREATING INFLAMMATORY CONDITIONS OF THE BOWEL

• US 20100035852A1
• Filed: 08/05/2009
• Published: 02/11/2010
• Est. Priority Date: 08/05/2008
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Showalter, Hollis, Koga, Hiroyuki, Teitelbaum, Daniel H., Lucas, Peter, Larsen, Scott
• Granted Patent: US 8,293,776 B2
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 33/566 using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

The present invention provides compositions and methods for treating inflammatory conditions (e.g., of the bowel). In particular, the present invention provides methods of treating (e.g., therapeutically and/or prophylactically treating) inflammatory conditions (e.g., of the bowel), compositions useful for such methods (e.g., antagonists and/or inhibitors of angiotensin II (AngII) receptor Type 1a (AT1a)), and methods of identifying, characterizing and/or optimizing such compositions. Compositions and methods of the present invention find use in, among other things, clinical (e.g. therapeutic and preventative medicine) and research applications.

Claims

1. A method of treating a subject, comprising:

a) providing;

i) a subject with inflammatory bowel disease, and

ii) a composition comprising an angiotensin II (AngII) receptor Type 1a (AT1a) antagonist, or derivative thereof, that is poorly cell permeable and poorly absorbed through the gastrointestinal tract; and

b) administering said composition to said subject under conditions such that the severity of inflammatory bowel disease is reduced in said subject.

2. The method of claim 1, wherein said composition comprising an AT1a antagonist or derivative thereof is suspended in polyethylene glycol.

3. The method of claim 1, wherein said composition comprising an AT1a antagonist or derivative thereof further comprises a corticosteroid.

4. The method of claim 1, wherein said AT1a antagonist or derivative thereof prevents fibrosis in the intestine of said subject.

5. The method of claim 1, wherein said composition comprising an AT1a antagonist or derivative thereof is enterally administered.

6. The method of claim 5, wherein administering enterally comprises rectal administration.

7. The method of claim 6, wherein said rectal administration comprises an enema.

8. The method of claim 5, wherein administering enterally comprises oral administration.

9. The method of claim 1, wherein said inflammatory bowel disease is selected from the group consisting of Crohn'"'"'s disease, celiac disease, ulcerative colitis, diverticulitis, pouchitis, or chronic diarrhea.

10. The method of claim 1, wherein said AT1a antagonist or derivative thereof is selected from the group consisting of a derivative of losartan and a derivative of candesartan.

11. The method of claim 1, wherein reduction of the severity of inflammatory bowel disease in said subject is detectable by a decrease in the clinical severity of colitis in said subject.

12. The method of claim 1, wherein reduction of the severity of inflammatory bowel disease in said subject is detectable by a reduction in histologic score in said subject.

16. The method of claim 11, wherein said composition comprising an AT1a antagonist or derivative thereof is administered via an enteric route.

13. A method of treating a subject comprising:

a) providing;

i) a subject at risk for inflammatory bowel disease, and

ii) a composition comprising an AT1a antagonist or derivative thereof, and;

b) administering said composition to said subject so as to prevent said subject from experiencing symptoms of inflammatory bowel disease.

14. The method of claim 13, wherein said administration of said composition delays the onset of symptoms of inflammatory bowel disease, wherein said symptoms are selected from the group consisting of heme positive stools and the loss of body weight.

15. The method of claim 13, wherein said composition comprising an AT1a antagonist or derivative thereof further comprises a corticosteroid.

17. A composition comprising an AT1a antagonist or derivative thereof and an angiotensin converting enzyme inhibitor.

18. The composition of claim 17, further comprising one or more other agents selected from the group consisting of polyethylene glycol and a corticosteroid.

19. The composition of claim 17, wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, ceranapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, moexipril, perindopril, perindoprilat, quinapril, quinaprilat, ramipril, saralasin acetate, spirapril, temocapril, trandolapril, fasidotrilat, (R)-2-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(methylthio)propanoic acid, idrapril, Pyrido(2,1-a)(2)benzazepine-4-carboxylic acid, 7-((2-(acetylthio)-1-oxo-3-phenylpropyl)amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxo-, (4S-(4-alph, 7alpha(R*), 12bbeta)), and 4-[[4-amino-6-(cyclohexylmethoxy)pyrimidin-2-yl]amino]benzenesulfonamide.

20. A method of identifying an AT1a antagonist derivative that possesses biological antagonist activity comprising:

a) providing;

1) an AT1a antagonist derivative; and

2) cells comprising an angiotensin type 1 receptor type 1a (AT1a) receptor and a NF-kB sensitive reporter; and

b) exposing said cells to angiotensin II (Ang II) in the presence and absence of said AT1a antagonist derivative; and

c) characterizing the activity of said NF-kB sensitive reporter; and

d) correlating said activity of said NF-kB sensitive reporter with the biological antagonistic activity of said AT1a antagonist derivative.