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 method of treating Celiac Sprue and/or dermatitis herpetiformis, the method comprising:
 administering to a patient an effective dose of a tTGase inhibitor;   wherein said tTGase inhibitor attenuates gluten toxicity in said patient.   
     
     
         2 . The method of  claim 1 , wherein said tTGase inhibitor is or comprises a dihydroisoxazole moiety or is an analog of isatin. 
     
     
         3 . The method of  claim 1 , wherein said tTGase inhibitor is administered with a glutenase. 
     
     
         4 . The method according to  claim 1 , wherein said tTGase inhibitor is administered orally. 
     
     
         5 . The method according to  claim 1 , wherein said tTGase inhibitor is contained in a formulation that comprises an enteric coating. 
     
     
         6 . A formulation for use in treatment of Celiac Sprue and/or dermatitis herpetiformis, comprising:
 an effective dose of a tTGase inhibitor and a pharmaceutically acceptable excipient.   
     
     
         7 . The formulation of  claim 6 , wherein said tTGase inhibitory moiety is: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  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 R 2  can additionally be selected from the group consisting of LPYPQPQLPY, LPFPQPQLPF-NH 2 , LPYPQPQLP, LPYPQPQLPYPQPQPF, LP-X 2-15 , where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a C-terminal proline; R 3  is selected from F, I, Cl, and Br; n is from 0 to 10; and X is selected from the group consisting of O and NH. 
       
     
     
         8 . The formulation of  claim 7 , wherein R 1  is selected from the group consisting of BnO, Me, Cbz, Fmoc, Boc, PQP, Ac-PQP, PQPQLPYPQP, Ac-PQPQLPFPQP, QLQPFPQP, LQLQPFPQPLPYPQP, X 2-15 -P, where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a N-terminal proline. 
     
     
         9 . The formulation of  claim 7 , wherein R 2  is selected from the group consisting of (S)-BO, (S)—CO 2 Me, (S)-Me, (R)-Bn, (S)—CH 2 CONHBn, (S)-(1H-inol-yl)-methyl, (S)-(4-hydrohy-phenyl)-methyl, OMe, OtBu, Gly, Gly-NH 2 , LPY, LPF-NH 2 . 
     
     
         11 . The formulation inhibitor of  claim 7 , 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; (S)-2-Benzyloxycarbonylamino-4-[(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-butyric acid methyl ester; (S)-2-Benzyloxycarbonylamino-N-(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-succinamic acid methyl ester; (S)-2-Benzyloxycarbonylamino-3-phenyl-propionic acid 3-bromo-4,5-dihydro-isoxazol-5-ylmethyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester; (S)-2-Acetylamino-N-(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-3-phenyl-propionamide; {(R)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester; {(S)-2-Benzylcarbamoyl-1-[(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester; [(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-carbamic acid benzyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester; and [(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-methyl-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid benzyl ester.   
     
     
         12 . The method according to  claim 1 , wherein said tTGase inhibitor has the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  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 R 2  can additionally be selected from the group consisting of LPYPQPQLPY, LPFPQPQLPF-NH 2 , LPYPQPQLP, LPYPQPQLPYPQPQPF, LP-X 2-15 , where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a C-terminal proline; R 3  is selected from F, I, Cl, and Br; n is from 0 to 10; and X is selected from the group consisting of O and NH. 
       
     
     
         13 . The method of  claim 12 , wherein R 1  is selected from the group consisting of BnO, Me, Cbz, Fmoc, Boc, PQP, Ac-PQP, PQPQLPYPQP, Ac-PQPQLPFPQP, QLQPFPQP, LQLQPFPQPLPYPQP, X 2-15 -P, where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a N-terminal proline. 
     
     
         14 . The method of  claim 12 , wherein R 2  is selected from the group consisting of (S)-Bn, (S)—CO 2 Me, (S)-Me, (R)-Bn, (S)—CH 2 CONHBn, (S)-(1H-inol-yl)-methyl, (S)-(4-hydrohy-phenyl)-methyl, OMe, OtBu, Gly, Gly-NH 2 , LPY, LPF-NH 2 . 
     
     
         15 . The method according to  claim 12 , 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; (S)-2-Benzyloxycarbonylamino-4-[(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-butyric acid methyl ester; (S)-2-Benzyloxycarbonylamino-N-(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-succinamic acid methyl ester; (S)-2-Benzyloxycarbonylamino-3-phenyl-propionic acid 3-bromo-4,5-dihydro-isoxazol-5-ylmethyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester; (S)-2-Acetylamino-N-(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-3-phenyl-propionamide; {(R)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester; {(S)-2-Benzylcarbamoyl-1-[(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester; [(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-carbamic acid benzyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester; and [(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-methyl-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid benzyl ester.   
     
     
         16 . A tTGase inhibitor of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  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 R 2  can additionally be selected from the group consisting of LPYPQPQLPY, LPFPQPQLPF-NH 2 , LPYPQPQLP, LPYPQPQLPYPQPQPF, LP-X 2-15 , where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a C-terminal praline; R 3  is selected from F, I, Cl, and Br; n is from 0 to 10; and X is selected from the group consisting of O and NH,
 other than {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester. 
 
       
     
     
         17 . The tTGase inhibitor of  claim 16 , wherein R 1  is selected from the group consisting of BnO, Me, Cbz, Fmoc, Boc, PQP, Ac-PQP, PQPQLPYPQP, Ac-PQPQLPFPQP, QLQPFPQP, LQLQPFPQPLPYPQP, X 2-15 -P, where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a N-terminal proline. 
     
     
         18 . The tTGase inhibitor of  claim 16 , wherein R 2  is selected from the group consisting of (S)-Bn, (S)—CO 2 Me, (S)-Me, (R)-Bn, (S)—CH 2 CONHBn, (S)-(1H-inol-yl)-methyl, (S)-(4-hydrohy-phenyl)-methyl, OMe, OtBu, Gly, Gly-NH 2 , LPY, LPF-NH 2 . 
     
     
         19 . The tTGase inhibitor of  claim 16 , wherein said tTGase inhibitor is selected from the group consisting of:
 (S)-2-Benzyloxycarbonylamino-4-[(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-butyric acid methyl ester; (S)-2-Benzyloxycarbonylamino-N-(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-succinamic acid methyl ester; (S)-2-Benzyloxycarbonylamino-3-phenyl-propionic acid 3-bromo-4,5-dihydro-isoxazol-5-ylmethyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester; (S)-2-Acetylamino-N-(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-3-phenyl-propionamide; {(R)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester; {(S)-2-Benzylcarbamoyl-1-[(3-bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester; [(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-carbamic acid benzyl ester; {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester; and [(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-methyl-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid benzyl ester.