Peptidomimetic Inhibitors of Post-Proline Cleaving Enzymes

• US 20110082108A1
• Filed: 06/01/2010
• Published: 04/07/2011
• Est. Priority Date: 11/26/2001
• Status: Abandoned Application

• Current Assignee: Bach Biosciences, LLC
• Original Assignee: Trustees of Tufts College
• Inventors: Bachovchin, William W.
• Application Number:
  US12/791,517
• Publication Number:
  US 20110082108A1
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

The present invention relates to inhibitors of post-proline cleavage enzymes, such as inhibitors of dipeptidyl peptidase IV, as well as pharmaceutical compositions thereof, and methods for using such inhibitors. In particular, the inhibitors of the present invention are improved over those in the prior art by selection of particular classes of side chains in the P1 and/or P2 position of the inhibitor. The compounds of the present invention can have a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.

Claims

1. A protease inhibitor represented by Formula I:

5. The inhibitor of any of claims 1-4, wherein W represents —

CN, —

CH═

NR₅,

6. The inhibitor of claim 1 or 2, wherein R_4a, R_4b and R_4c each independently represent a small hydrophobic group.

7. The inhibitor or claim 6, wherein R_4a, R_4b and R_4c, are independently selected from the group consisting of halogens, lower alkyls, lower alkenyls, and lower alkynyls.

8. The inhibitor of claim 1 or 2, wherein R_4a and R_4b each represent hydrogen, and R_4c represents a small hydrophobic group.

9. The inhibitor of claim 1, 2 or 5, wherein R_4a and R_4b each represent hydrogen, and R_4c represents a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

10. The inhibitor of claim 9, wherein R_4c represents a C3-C8 cycloalkyl.

11. The inhibitor of any of claims 1, 3 or 9, wherein R₂ is absent, or represents —

OH.

12. The inhibitor of any of claims 1-6, 9 or 11, wherein R_3a a hydrogen and R_3b is absent.

13. The inhibitor of any of claims 1-12, wherein W represents:

14. The inhibitor of claim 13, wherein R₅ is a hydrogen or —

C(X₁)(X₂)X₃, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are also fluorine.

15. The inhibitor of any of claims 1-12, wherein R₁ is an amino acid residue or a peptidyl moiety which is a substrate for a protease.

16. The inhibitor of any of the foregoing claims, wherein the protease inhibitor inhibits DPIV with a Ki of 50 nm or less.

17. The inhibitor of any of the foregoing claims, which inhibitor is orally active.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a protease inhibitor of any of claims 1-17, or a pharmaceutically acceptable salt or prodrug thereof.

19. Use of an inhibitor of any of claims 1-17 in the manufacture of a medicament for inhibiting a post-proline cleaving enzyme in vivo.

20. The use of claim 19, wherein the inhibitor increases plasma concentrations of a peptide hormone selected from glucagon like peptide, NPY, PPY, secretin, GLP-1, GLP-2, and GIP.

21. Use of an inhibitor of any of claims 1-17 in the manufacture of a medicament for regulating glucose metabolism.

22. The use of claim 21, for regulating glucose metabolism of a patient suffering from Type II diabetes, insulin resistance, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

23. A method for inhibiting the proteolytic activity of a post-proline cleaving enzyme, comprising contacting the enzyme with a protease inhibitor of any of claims 1-17.

24. A packaged pharmaceutical comprising:

a preparation of any of the protease inhibitor of claims 1-17;

a pharmaceutically acceptable carrier; and

instructions, written and/or pictorial, describing the use of the preparation for inhibiting a post-proline cleaving enzyme in vivo.

25. A packaged pharmaceutical comprising:

a preparation of any of the protease inhibitor of claims 1-17;

a pharmaceutically acceptable carrier; and

instructions, written and/or pictorial, describing the use of the preparation for regulating glucose metabolism.

26. The packaged pharmaceutical of claim 25, wherein the protease inhibitor is co-formulated with, or co-packaged with, insulin and/or an insulinotropic agent.

27. The packaged pharmaceutical of claim 25, wherein the protease inhibitor is co-formulated with, or co-packaged with, an M1 receptor antagonist, a prolactin inhibitor, agents acting on the ATP-dependent potassium channel of n-cells, metformin, and/or glucosidase inhibitors.

2. A protease inhibitor represented by Formula III:

3. A protease inhibitor represented by Formula IV:

4. A protease inhibitor represented by Formula VI: