Soft protease inhibitors and pro-soft forms thereof

1. A method for inhibiting the proteolytic activity of a post-proline-cleaving enzyme, wherein said enzyme is a mammalian dipeptidyl peptidase IV (DPP IV), comprising contacting said enzyme with an effective amount of a thioxam compound represented by:

or a pharmaceutically acceptable salt thereof;

wherein

A represents a 4-8 membered heterocycle including the N and the Cα carbon;

R 1 represents a C-terminally linked amino acid residue or amino acid analog, wherein the amide bond between R 1 and N is replaced by a thioxamide bond;

R 2 is absent or represents one or more substitutions to the ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, carboxyl, ester, formate, ketone, thiocarbonyl, thioester, thioacetate, thioformate, amino, acylamino, amido, nitro, sulfate, sulfonate, sulfonamido, —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 7 , azido, cyano, isocyanato, thiocyanato, isothiocyanato, cyanato,

 or —C≡C—R 8 ;

R 3 represents hydrogen or a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, nitro, sulfate, sulfonate, a sulfonamido, —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 7 , azido, cyano, isocyanato, thiocyanato, isothiocyanato, cyanato,

 or —C≡C—R 8 ;

R 7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;

R 8 represents hydrogen, —CH 3 , or —(CH 2 ) n —CH 3 ;

Y 1 and Y 2 , independently, are OH, or a group capable of being hydrolyzed to a hydroxyl group, or Y 1 and Y 2 are connected via a ring having from 5 to 8 atoms in the ring structure which is capable of being hydrolyzed to two hydroxyl groups;

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.

2. The method of claim 1 , wherein Y 1 and Y 2 , independently, are OH.

3. The method of claim 2 , wherein said compound is represented by:

4. The method of claim 1 , wherein R 2 is absent, or represents lower alkyl or halogen.

5. The method of claim 1 , wherein R 3 is hydrogen.

6. The method of claim 1 , wherein the Cα carbon exists substantially in the R configuration.

7. The method of claim 1 , wherein the Cα carbon exists substantially in the S configuration.

8. The method of claim 1 , wherein the Cα carbon exists in a racemic mixture of R and S configurations.

9. The method of claim 1 , wherein R 1 is a proline, glutamate, or alanine residue.

10. The method of claim 1 , wherein R 1 is an alanine residue.

11. The method of claim 1 , wherein the compound is selected from the group consisting of:

and enantiomers, diastereomers, and salts thereof.

12. The method claim 1 , wherein the compound inhibits dipeptidyl peptidase IV with a Ki of 50 nM or less.

13. The method of claim 12 , wherein the compound inhibits dipeptidyl peptidase VIII and dipeptidyl peptidase IX with a Ki of 100 microM or greater.

14. A method of regulating glucose metabolism in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a thioxam compound represented by:

or a pharmaceutically acceptable salt thereof

wherein

A represents a 4-8 membered heterocycle including the N and the Cα carbon;

R 1 represents a C-terminally linked amino acid residue or amino acid analog, wherein the amide bond between R 1 and N is replaced by a thioxamide bond;

R 2 is absent or represents one or more substitutions to the ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, carboxyl, ester, formate, ketone, thiocarbonyl, thioester, thioacetate, thioformate, amino, acylamino, amido, nitro, sulfate, sulfonate, sulfonamido, —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) m —O—(CH 2 ) m —R 7 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 7 , azido, cyano, isocyanato, thiocyanato, isothiocyanato, cyanato,

 or —C≡C—R 8 ;

R 3 represents hydrogen or a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, nitro, sulfate, sulfonate, a sulfonamido, —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 7 , azido, cyano, isocyanato, thiocyanato, isothiocyanato, cyanato,

 or —C≡C—R 8 ;

R 7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;

R 8 represents hydrogen, —CH 3 , or —(CH 2 ) n —CH 3 ;

Y 1 and Y 2 , independently, are OH, or a group capable of being hydrolyzed to a hydroxyl group, or Y 1 and Y 2 are connected via a ring having from 5 to 8 atoms in the ring structure which is capable of being hydrolyzed to two hydroxyl groups;

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.

15. The method of claim 14 , wherein the patient is suffering from Type II diabetes, insulin resistance, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

16. The method of claim 14 , further comprising administering to said patient a therapeutically effective amount of insulin, an insulinotropic agent, or both.

17. The method of claim 14 , further comprising administering to said patient a therapeutically effective amount of an M1 receptor antagonist, a prolactin inhibitor, an agent acting on the ATP-dependent potassium channel of β-cells, metformin, a glucosidase inhibitor, or a combination of any of them.