Claims for Patent: 7,459,428

Summary for Patent: 7,459,428

Title:	Method of regulating glucose metabolism, and reagents related thereto
Abstract:	One aspect of the present invention relates to a method for treating Type II diabetes in an animal, comprising conjointly administering to the animal metformin and an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof in an amount sufficient to treat Type II diabetes of the animal.
Inventor(s):	William W. Bachovchin, Andrew G. Plaut, Daniel Drucker
Assignee:	1149336 Ontario Inc, Tufts Medical Center Inc, Tufts University, Arisaph Pharmaceuticals Inc
Application Number:	US11/487,947
Patent Claims:	1. A method for treating Type II diabetes in an animal, comprising conjointly administering to the animal metformin and an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof in an amount sufficient to treat Type II diabetes, wherein the amount of said inhibitor of dipeptidylpeptidase IV or pharmaceutically acceptable salt thereof is not sufficient to suppress the immune system of the animal. 2. The method of claim 1, wherein the inhibitor reduces insulin resistance, glucose intolerance, hyperglycemia, or hyperinsulinemia. 3. The method of claim 1, wherein the inhibitor has an EC50 for modification of glucose metabolism which is at least one order of magnitude less than its EC50 for immunosuppression. 4. The method of claim 1, wherein the inhibitor has a Ki for dipeptidylpeptidase IV inhibition of 10 nM or less. 5. The method of claim 1, wherein the inhibitor has a Ki for dipeptidylpeptidase IV inhibition of 1.0 nM or less. 6. The method of claim 1, wherein the inhibitor has a molecular weight less than 7500 amu. 7. The method of claim 1, wherein the inhibitor is administered orally. 8. The method of claim 1, wherein the inhibitor is a peptidomimetic of a peptide selected from the group consisting of Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala. 9. The method of claim 1, wherein the inhibitor is represented by Formula I: wherein, A represents a 4-8 membered heterocycle including a N and a Cα carbon; Z represents C or N; W represents CN, —CH═NR5, R1 represents a C-terminally linked amino acid residue, a C-terminally linked amino acid analog, a C-terminally linked peptide, a C-terminally linked peptide analog, an amino-protecting group R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)mOH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; if Z is N, R3 represents a hydrogen; if Z is C, R3 represents a hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2 m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7, R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)mR7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)mS-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alikyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; Y1 and Y2 independently each represent a hydroxyl group or a group capable of being hydrolyzed to a hydroxyl group, or Y1 and Y2 together, including the boron to which they are bound, form a 5-8 membered cyclic derivative which is capable of being hydrolyzed to hydroxyl groups; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 10. The method of claim 9, wherein the ring A is represented by the formula: wherein, k is an integer of 1 or 2. 11. The method of claim 9, wherein W represent 12. The method of claim 9, wherein R1 represents wherein, R36 represents a small hydrophobic group and R38 is hydrogen, or, R36 and R38 together form a 4-7 membered heterocycle including the N and the Cα carbon, as defined for A above; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. 13. The method of claim 9, wherein R2 is absent. 14. The method of claim 9, wherein R3 is a hydrogen. 15. The method of claim 9, wherein R5 is a hydrogen. 16. The method of claim 9, wherein X1 is a fluorine, and X2 and X3, if halogens, are fluorine. 17. The method of claim 9, wherein the inhibitor is represented by Formula (II): wherein, R1 represents a C-terminally linked amino acid residue a C-terminally linked amino acid analog, a C-terminally linked peptide, a C-terminally linked peptide analog, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; and R11 and R12 each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R11 and R12 taken together with the O—B—O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure. 18. The method of claim 9, wherein the inhibitor is represented by Formula III: wherein, R1 represents a C-terminally linked amino acid residue a C-terminally linked amino acid analog, a C-terminally linked peptide, a C-terminally linked peptide analog R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle. 19. The method of claim 1, wherein the inhibitor is represented by the Formula IV: wherein, R1 represents a C-terminally linked amino acid residue a C-terminally linked amino acid analog, a C-terminally linked peptide, a C-terminally linked peptide analog, R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)mS-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alikyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; X1, X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 20. The method of claim 9, wherein the inhibitor is represented by the Formula Xa or Xb: wherein, A represents a 4- to 8-membered heterocycle including a N and a Cα carbon; W represents CN, —CHNR5, R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7, R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R32 is a small hydrophobic group; R30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; Y1 and Y2 independently represent a hydroxyl group or a group capable of being hydrolyzed to a hydroxyl group, or Y1 and Y2 together, including the boron to which they are bound, form a 5-8 membered cyclic derivative which is capable of being hydrolyzed to hydroxyl groups; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 21. The method of claim 1, wherein said conjointly administering is achieved by simultaneous dosing of the individual components. 22. The method of claim 1, wherein said conjointly administering is achieved by sequential dosing of the individual components. 23. The method of claim 1, wherein said conjointly administering is achieved by separate dosing of the individual components. 24. The method of claim 1, wherein said conjointly administering is achieved by dosing the individual components in the same composition.