Soft protease inhibitors and pro-soft forms thereof
The invention provides compounds and methods for inhibiting proteases. One aspect of the invention features pro-soft inhibitors which react with an activating protease to release an active inhibitor moiety in proximity to a target protease. In certain instances, compounds inhibit proteasomes and/or post-proline cleaving enzymes (PPCE), such as dipeptidyl peptidase IV. The compounds of the invention provide a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.
1. A compound represented by:
or a pharmaceutically acceptable salt thereof;
wherein
R 1 represents hydrogen, a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog;
R 9 represents hydrogen or alkyl;
R 10 represents the side chain of a natural or non-natural amino acid;
R 11 represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, or the side chain of a natural or non-natural amino acid; and
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.
2. The compound of claim 1 , wherein Y 1 and Y 2 are OH.
3. The compound of claim 2 , wherein said compound is represented by:
4. The compound of claim 1 , wherein the Cα carbon exists substantially in the S configuration.
5. The compound of claim 1 , wherein the Cα carbon exists in a racemic mixture of R and S configurations.
6. The compound of claim 1 , wherein R 1 is a proline, glutamate, or alanine residue.
7. The compound of claim 1 , wherein R 1 is an alanine residue.
8. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
9. A compound selected from the group consisting of
and pharmaceutically acceptable salts thereof.
10. A compound represented by
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is a protease inhibitor.
12. The compound of claim 11 , wherein the compound inhibits dipeptidyl peptidase VIII and IX with a Ki of 100 μM or greater.
13. A compound represented by:
or a pharmaceutically acceptable salt thereof;
wherein
W represents
R 1 represents a C-terminally linked peptide or peptide analog which is a substrate for an activating enzyme;
R 3 represents a hydrogen or lower alkyl;
R 4 represents hydrogen, halogen, lower alkyl, lower alkenyl, or lower alkynyl;
Y 1 and Y 2 are independently 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;
R 10 represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aralkyl,
heteroaralkyl, aryl, heteroaryl, or the side chain of a natural or non-natural amino acid.
14. The compound of claim 13 , wherein R 4 represents hydrogen or lower alkyl.
15. The compound of claim 13 , wherein R 5 represents H or alkyl.
16. The compound of claim 13 , wherein said compound is represented by:
17. The compound of claim 16 , wherein R 4 represents hydrogen or lower alkyl.
18. The compound of claim 13 , wherein R 1 is:
19. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
20. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier;
and a compound of claim 1 .
21. 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 a compound of claim 1 .
22. A method of regulating glucose metabolism in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
23. The method of claim 22 , wherein the patient is suffering from Type II diabetes, insulin resistance, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.
24. The method of claim 22 , further comprising administering to said patient a therapeutically effective amount of insulin, an insulinotropic agent or both.
25. The method of claim 22 , 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.