Drug Therapy for Celiac Sprue

Abstract

Administering an effective dose of a tTGase inhibitor to a Celiac or dermatitis herpetiformis patient reduces the toxic effects of toxic gluten oligopeptides, thereby attenuating or eliminating the damaging effects of gluten.

1 . A tTGase inhibitor of the formula: 
       
         
           
           
               
               
           
         
       
       wherein Ri and R2 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, alkoxy, alkylthio, arakyl, aralkenyl, halo, haloalkyl, haloalkoxy, heterocyclyl, and heterocyclylalkyl groups, an amino acid, a peptide, a peptidomimetic, or a peptidic protecting group; wherein R2 can additionally be selected from the group consisting of LPYPQPQLPY, LPFPQPQLPF-NH 2 , LPYPQPQLP, LPYPQPQLPYPQPQPF, where X2-15 is a peptide consisting of any 2-15 amino acid residues followed by a C-terminal proline; R3 is selected from F, and Br; n is from 0 to 10; and X is selected from the group consisting of O and NH, other than acid benzyl ester. 
     
     
         2 . The inhibitor of  claim 1 , wherein Ri is selected from the group consisting of BnO, Me, Cbz, Fmoc, Boc, PQP, PQPQLPYPQP, QLQPFPQP, LQLQPFPQPLPYPQP, where X2-15 is a peptide consisting of any 2-15 amino acid residues followed by a N-terminal proline. 
     
     
         3 . The inhibitor of  claim 1 , wherein R2 is selected from the group consisting of hydrohy-phenyl)-methyl, OMe, OtBu, LPY, LPF-NH 2 . 
     
     
         4 . The inhibitor of  claim 1 , wherein is Br. 
     
     
         5 . The inhibitor of  claim 1 , wherein said tTGase inhibitor is selected from the group consisting of: {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester; 5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-butyric acid methyl ester; (S)-2-Benzyloxycarbonylamino-acid methyl ester; (S)-2-ester; acid benzyl ester; propionamide; acid benzyl ester; acid benzyl ester; [(S)-1-[(3-Bromo-4,5-acid benzyl ester; carbamic acid benzyl ester; acid benzyl ester; 5-dihydro-isoxazol-5-ylmethyl)-3-phenyl-urea; chloro-5-trifluoromethyl-phenyl)-urea; chloro-2-trifluoromethyl-phenyl)-urea; fluoro-phenyl)-urea; urea; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl}-carbamic acid benzyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-acid benzyl ester; 5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl}-carbamic acid benzyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylamethyl)-carbamoyl]-2-(5-hydroxy-1H-indol-3-yl)-ethyl}-carbamic acid benzyl ester; acid pyridin-4-ylmethyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl}-carbamic acid ester; acid phenethyl ester; 5-dihydro-ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-(4-hydroxy-[b]thiophen-2-ylmethyl ester; Bromo-4, carbamic acid 1, [b]thiophen-2-ylmethyl ester. 
     
     
         6 . A tTGase inhibitor of the formula: 
       
         
           
           
               
               
           
         
       
       where R2 and R3 are independently selected from H, a halo group, alkyl, aryl, and NO2. 
     
     
         7 . The tTGase inhibitor of  claim 11 , wherein said inhibitor is selected from the group consisting of: 2,3-Dioxo-2, acid propylamide; 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid benzylamide; (S)-1-(2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester; (S)-2-(2,3-Dioxo-2,3-dihydro-1H-indole-5-; 3-dioxo-2,3-; 2,3-dione; 3-dione 8. A formulation for use in treatment of Celiac Sprue and/or dermatitis herpetiformis, comprising: an effective dose of the tTGase inhibitor according to any of  claims 1 - 7  and a pharmaceutical acceptable excipient. 
     
     
         8 . A formulation for use in treatment of Celiac Sprue and/or dermatitis herpetiformis, comprising:
 an effective dose of the tTGase inhibitor according to any of  claim 1  and a pharmaceutically acceptable excipient.   
     
     
         9 . A method of treating Celiac Sprue and/or dermatitis herpetiformis, the method comprising: administering to a patient an effective dose of a formulation according to  claim 8 ; wherein said tTGase inhibitor attenuates gluten toxicity in said patient 
     
     
         10 . The method of  claim 9 , wherein said formulation is administered with a glutenase. 
     
     
         11 . The method according to  claim 9 , wherein said formulation is administered orally. 
     
     
         12 . The method according to  claim 9 , wherein said formulation comprises an enteric coating.