Peptidomimetic macrocycles

• US 9,957,299 B2
• Filed: 04/21/2016
• Issued: 05/01/2018
• Est. Priority Date: 08/13/2010
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Guerlavais, Vincent, Kawahata, Noriyuki
• Primary Examiner(s): McDonald, Jennifer Pitrak
• Assistant Examiner(s): Coffa, Sergio
• Application Number:
  US15/135,098
• Publication Number:
  US 20160257716A1
• Time in Patent Office: 740 Days
• Field of Search: None
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/4746 p53
• 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 disease.

Claims

1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least 60% identical to the amino acid sequence of:

SEQ ID NO. 163.

2. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 80% identical to the amino acid sequence of:

SEQ ID NO. 163.

3. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 90% identical to the amino acid sequence of:

SEQ ID NO. 163.

4. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 95% identical to the amino acid sequence of:

SEQ ID NO. 163.

5. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is:

SEQ ID NO. 163.

6. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises a helix.

7. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an α

-helix.

8. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an α

,α

-disubstituted amino acid.

9. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises a crosslinker linking the α

-positions of at least two amino acids within the peptidomimetic macrocycle.

10. The peptidomimetic macrocycle of claim 9, wherein at least one of the two amino acids is an α

,α

-disubstituted amino acid.

11. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle has the formula:

12. The peptidomimetic macrocycle of claim 11, wherein L does not include a thioether or a triazole.

13. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises a cross linker linking a backbone amino group of a first amino acid within the peptidomimetic macrocycle to a second amino acid within the peptidomimetic macrocycle.

14. The peptidomimetic macrocycle of claim 13, wherein the peptidomimetic macrocycle has the formula (IV) or (IVa):

15. The peptidomimetic macrocycle of claim 14, wherein L₁ and L₂ either alone or in combination do not include a thioether or a triazole.

16. The peptidomimetic macrocycle of claim 11, wherein L₁ and L₂ are independently alkylene, alkenylene or alkynylene.

17. The peptidomimetic macrocycle of claim 11, wherein L₁ and L₂ are independently C₃-C₁₀ alkylene or C₃-C₁₀ alkenylene.

18. The peptidomimetic macrocycle of claim 17, wherein L₁ and L₂ are independently C₃-C₆ alkylene or C₃-C₆ alkenylene.

19. The peptidomimetic macrocycle of claim 11, wherein R₁ and R₂ are H.

20. The peptidomimetic macrocycle of claim 11, wherein R₁ and R₂ are independently alkyl.

21. The peptidomimetic macrocycle of claim 11, wherein R₁ and R₂ are methyl.

22. A pharmaceutical composition comprising the peptidomimetic macrocycle of claim 1.