Peptidomimetic macrocycles

• US 9,096,684 B2
• Filed: 10/18/2012
• Issued: 08/04/2015
• Est. Priority Date: 10/18/2011
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Kawahata, Noriyuki, Guerlavais, Vincent, Samant, Manoj
• Primary Examiner(s): Steele, Amber D
• Assistant Examiner(s): Milton, Schuyler
• Application Number:
  US13/655,378
• Publication Number:
  US 20130123169A1
• Time in Patent Office: 1,020 Days
• Field of Search: None
• US Class Current: 1/1
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 14/60 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin

Abstract

The present invention provides peptidomimetic macrocycles capable of modulating growth hormone levels 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 about 60% identical to GHRH 1-29, comprising at least two macrocycle-forming linkers, wherein the first of said two macrocycle-forming linkers connects a first amino acid to a second amino acid, and the second of said two macrocycle-forming linkers connects a third amino acid to a fourth amino acid, wherein the peptidomimetic macrocycle comprises an α

,α

-disubstituted amino acid.

2. The peptidomimetic macrocycle of claim 1, comprising two macrocycle-forming linkers.

3. The peptidomimetic macrocycle of claim 1, wherein each of said macrocycle-forming linkers connects a pair of amino acids corresponding to one of the following locations of amino acids:

4 and 8;

5 and 12;

8 and 12;

8 and 15;

9 and 16;

12 and 16;

12 and 19;

15 and 22;

18 and 25;

21 and 25;

21 and 28;

22 and 29;

25 and 29 of GHRH 1-29.

4. The peptidomimetic macrocycle of claim 3, wherein each of said macrocycle-forming linkers connects a pair of amino acids corresponding to one of the following locations of amino acids:

4 and 8;

5 and 12;

12 and 19;

15 and 22;

18 and 25;

21 and 25;

21 and 28 of GHRH 1-29.

5. The peptidomimetic macrocycle of claim 3, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acids:

4 and 8;

5 and 12;

8 and 12;

8 and 15;

9 and 16;

12 and 16;

or 12 and 19; and

the second macrocycle-forming linker connects amino acid pairs 15 and 22;

18 and 25;

21 and 25;

21 and 28;

22 and 29;

or 25 and 29 of GHRH 1-29.

6. The peptidomimetic macrocycle of claim 3, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acids:

4 and 8;

5 and 12;

or 12 and 19; and

the second macrocycle-forming linker connects amino acid pairs 15 and 22;

18 and 25;

21 and 25;

or 21 and 28 of GHRH 1-29.

7. The peptidomimetic macrocycle of claim 3, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to amino acid locations 4 and 8 of GHRH 1-29, and the second macrocycle-forming linker connects a pair of amino acids corresponding to amino acid locations 21 and 25 of GHRH 1-29.

10. A peptidomimetic macrocycle of claim 1, comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Tables 1, 2 or 4.

11. The peptidomimetic macrocycle of claim 1, wherein the amino acid sequence of said peptidomimetic macrocycle is at least about 80% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Tables 1, 2 or 4.

12. The peptidomimetic macrocycle of claim 1, wherein the amino acid sequence of said peptidomimetic macrocycle is at least about 90% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Tables 1, 2 or 4.

13. The peptidomimetic macrocycle of claim 1, wherein the amino acid sequence of said peptidomimetic macrocycle is chosen from the group consisting of the amino acid sequences in Tables 1, 2 or 4.

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

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

-helix.

16. The peptidomimetic macrocycle of claim 1, wherein each amino acid connected by the macrocycle-forming linkers is an α

,α

-disubstituted amino acid.

17. The peptidomimetic macrocycle of any preceding claim, having the formula:

18. The peptidomimetic macrocycle of claim 17, wherein u is 2.

19. The peptidomimetic macrocycle of claim 18, having the Formula:

20. The peptidomimetic macrocycle of claim 19, wherein the sum of x+y+z is 2, 3 or 6.

21. The peptidomimetic macrocycle of claim 19, wherein the sum of x′

+y′

+z′

is 2, 3 or 6.

22. The peptidomimetic macrocycle of claim 17, wherein each of v and w is independently an integer from 1 to 10, 1 to 15, 1 to 20, or 1 to 25.

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

24. The peptidomimetic macrocycle of claim 23, wherein the peptidomimetic macrocycle has the formula (II) or (IIa):

25. The peptidomimetic macrocycle of claim 1, having the formula:

26. The peptidomimetic macrocycle of claim 25, wherein A, B, C, D, and E, taken together with the crosslinked amino acids connected by the macrocycle-forming linker L, form an amino acid sequence which is at least about 60% identical to an amino acid sequence of Table 1, 2, or 4.

33. The peptidomimetic macrocycle of claim 17, wherein R₁ and R₂ are independently H.

34. The peptidomimetic macrocycle of claim 17, wherein R₁ and R₂ are independently alkyl.

35. The peptidomimetic macrocycle of claim 17, wherein R₁ and R₂ are independently methyl.

36. The peptidomimetic macrocycle of claim 17, wherein R₁ and R₂ are independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-.

37. The peptidomimetic macrocycle of claim 17, wherein one of R₁ and R₂ is —

H, and the other of R₁ and R₂ is alkyl.

38. The peptidomimetic macrocycle of claim 1, wherein at least one of the first, second, third, and fourth amino acids is the α

,α

-disubstituted amino acid.

8. A peptidomimetic macrocycle comprising:

i) an amino acid sequence which is at least about 60% identical to GHRH 1-29; and

ii) a macrocycle-forming linker connecting a first amino acid to a second amino acid, wherein the peptidomimetic macrocycle comprises an α

,α

-disubstituted amino acid, and wherein the first and second amino acids are selected from amino acids corresponding to the following locations of amino acids;

4 and 8;

5 and 12;

8 and 12;

8 and 15;

9 and 16;

12 and 16;

12 and 19;

15 and 22;

18 and 25;

21 and 25;

21 and 28;

22 and 29 of GHRH 1-29.

9. The peptidomimetic macrocycle of claim 8, wherein the macrocycle-forming linker connects amino acids corresponding to amino acid locations 12 and 19 of GHRH 1-29.

27. A peptidomimetic macrocycle comprising an amino acid sequence of formula:

28. The peptidomimetic macrocycle of claim 27, wherein each macrocycle-forming linker connects one of the following pairs of amino acids:

X4 and X8;

X5 and X12;

X8 and X12;

X8 and X15;

X9 and X16;

X12 and X16;

X12 and X19;

X15 and X22;

X18 and X25;

X21 and X25;

X21 and X28;

X22 and X29;

X25 and X29.

29. The peptidomimetic macrocycle of claim 28, wherein each macrocycle-forming linker connects one of the following pairs of amino acids:

X4 and X8;

X5 and X12;

X12 and X19;

X15 and X22;

X18 and X25;

X21 and X25;

X21 and X28.

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

31. The peptidomimetic macrocycle of claim 30, wherein L₁ and L₂ are independently C₃-C₁₀ alkylene or alkenylene.

32. The peptidomimetic macrocycle of claim 30, wherein L₁ and L₂ are independently C₃-C₆ alkylene or alkenylene.