Peptidomimetic macrocycles

• US 10,059,741 B2
• Filed: 07/01/2016
• Issued: 08/28/2018
• Est. Priority Date: 07/01/2015
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Annis, David Allen, Guerlavais, Vincent
• Primary Examiner(s): Ahmed, Hasan S
• Assistant Examiner(s): Yang, Kaipeen E
• Application Number:
  US15/200,422
• Publication Number:
  US 20170002042A1
• Time in Patent Office: 788 Days
• 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: A61P 31/12 Antivirals
• CPC Class Codes: C07K 14/11 Orthomyxoviridae, e.g. influenza virus
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/56 the cyclisation not occurring through 2,4-diamino-butanoic acid
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

The present invention provides novel peptidomimetic macrocycles and methods of using such macrocycles for the treatment of viral disease.

Claims

1. A peptidomimetic macrocycle or a pharmaceutically-acceptable salt thereof, wherein the peptidomimetic macrocycle:

(i) comprises two non-natural amino acids connected by a macrocycle-forming linker;

(ii) has an amino acid sequence Xaa0-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18; and

(iii) has at least about 60% sequence identity to a sequence of Table 1b;

wherein

Xaa0 is —

H or an N-terminal capping group;

each Xaa1-Xaa10 and Xaa12-Xaa15 is independently an amino acid;

Xaa11 is Ala;

each Xaa16 and Xaa17 is independently absent or an amino acid; and

Xaa18 is —

NH₂, —

OH, or a C-terminal capping group.

2. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the macrocycle-forming linker connects amino acids Xaa5 and Xaa9.

3. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the macrocycle-forming linker connects amino acids Xaa5 and Xaa12.

4. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle is a compound of Formula (Ia):

5. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle is a compound of Formula (Ib):

6. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle is a compound of Formula (I):

7. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle comprises an α

,α

-disubstituted amino acid.

8. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein each amino acid connected by the macrocycle-forming linker is an α

,α

-disubstituted amino acid.

9. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein u is 1.

10. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein x+y+z is 2, 3, 5 or 6.

11. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each v is independently an integer from 0-10.

12. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each v is 4.

13. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein [D]_v is -Asn₄-Val₃-Glu₂-Nle₁ (SEQ ID NO:

4).

14. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein [D]_v is -Asn₄-Val₃-Glu₂-Phe₁ (SEQ ID NO:

5).

15. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each w is independently an integer from 0-10.

16. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each w is 1, 2, 3, 4, 5, 6, or 8.

17. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each of the first two amino acids represented by E comprises an uncharged side chain or a negatively charged side chain.

18. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein the first, second, third or fourth amino acid represented by E comprises a hydrophobic side chain.

19. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 18, wherein the hydrophobic side chain is a small hydrophobic side chain.

20. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each E is independently an amino acid selected from the group consisting of Ala, D-Ala, Aib, Lys, Leu, Ser, Glu, and Gln.

21. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each L is independently alkylene, alkenylene, or alkynylene.

22. The peptidomimetic macrocycle of claim 6, wherein each R₁ and R₂ is independently —

H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo.

23. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each R₁ and R₂ is independently alkyl.

24. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each L and L′

independently has a formula -L₁-L₂-, wherein

each L₁ and L₂ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [—

R₄—

K—

R₄-]_n, each being optionally substituted with R₅;

each R₄ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is independently O, S, SO, SO₂, CO, CO₂ or CONR₃; and

each n is independently an integer from 1-5.

25. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 24, wherein each L₁ and L₂ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R₅.

26. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 24, wherein each L₁ and L₂ is independently alkylene, alkenylene or alkynylene.

27. The peptidomimetic macrocycle of claim 24, wherein each L₁ and L₂ is independently alkylene or alkenylene.

28. A pharmaceutical composition comprising the peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1 and a pharmaceutically acceptable excipient.

29. A method of treating influenza infection in a subject comprising administering to the subject the peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle has at least about 90% sequence identity to a sequence of Table 1b.

30. The method of claim 29, wherein the administering comprises administering subcutaneously or parenterally.

31. The method of claim 29, wherein the administering comprises administering a single dose of the peptidomimetic macrocycle.

32. A method of inhibiting the activity of the RNA-dependent RNA polymerase of an influenza virus in a subject comprising administering to the subject the peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle has at least about 90% sequence identity to a sequence of Table 1 b.