Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof

• US 9,243,038 B2
• Filed: 06/29/2012
• Issued: 01/26/2016
• Est. Priority Date: 07/01/2011
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Liu, David R., Maianti, Juan Pablo, Saghatelian, Alan, Kleiner, Ralph E.
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US14/130,336
• Publication Number:
  US 20140213515A1
• Time in Patent Office: 1,306 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 5/0215 containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
• CPC Class Codes: C07K 7/54 with at least one abnormal peptide link in the ring

Abstract

Macrocyclic compounds that specifically inhibit insulin degrading enzyme (IDE) are provided. Pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, polymorphs, tautomers, isotopically enriched forms, and prodrugs of the macrocyclic IDE inhibitors are also described. Pharmaceutical compositions are also provided. In vivo and in vitro methods of using the IDE inhibitor, and pharmaceutical compositions comprising the IDE inhibitor, for example, for the inhibition of IDE in a subject exhibiting aberrant IDE activity, impaired insulin signaling, or insulin resistance, for example, a subject having diabetes, are also provided.

Claims

1. A compound of Formula (V):

2. The compound of claim 1, wherein the compound is of Formula (VI):

3. The compound of claim 1, wherein n is 1.

4. The compound of claim 1, wherein m is 4.

5. The compound of claim 1, wherein the compound is of Formula (H):

6. The compound of claim 1, wherein R₂ is hydrogen or —

(CH₂)_q—

CH₃, wherein q is 0 or an integer between 1 and 10, inclusive.

7. The compound of claim 1, wherein R₅ is —

C(═

O)NH₂, or —

CH₂—

C(═

O)NH₂.

8. The compound of claim 1, wherein represents a double bond.

9. The compound of claim 1, wherein the compound is

10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, in an amount effective to inhibit IDE in a subject, and optionally a pharmaceutically acceptable carrier.

11. An in vitro method of inhibiting the activity of an insulin degrading enzyme (IDE) comprising contacting an IDE with the compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, in an amount effective to inhibit the activity of IDE.

12. An in vivo method of inhibiting the activity of an insulin degrading enzyme (IDE) comprising contacting an IDE with the compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, in an amount effective to inhibit the activity of IDE.

13. The method of claim 12, wherein the IDE molecule is contacted with the compound, the pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, or the composition in a subject.

14. The method of claim 13, wherein the subject exhibits impaired insulin signaling or insulin resistance.

15. The method of claim 14, wherein the subject has diabetes.

16. A method of treating a disease, disorder, or condition associated with impaired insulin signaling or insulin resistance, the method comprising administering a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, or isotopically enriched form thereof, to a subject in need thereof.

17. The compound of claim 8, wherein each of R_E, R_F, R_G, and R_I is hydrogen.

18. The compound of claim 17, wherein n is 1 and m is 4.

19. The compound of claim 18, wherein R₂ is hydrogen.

20. The compound of claim 19, wherein R₅ is —

C(═

O)—

N(R_J)₂.

21. The compound of claim 1, wherein R₅ is —

C(═

O)—

N(R_J)₂.

22. The compound of claim 1, wherein the compound is of Formula (VIII):

23. The method of claim 16, wherein the disease, disorder, or condition is diabetes.

24. The method of claim 16, wherein the disease, disorder, or condition is metabolic syndrome.