Peptidomimetic macrocycles

• US 10,308,699 B2
• Filed: 10/24/2016
• Issued: 06/04/2019
• 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): Skowronek, Karlheinz R.
• Assistant Examiner(s): Niebauer, Ronald T
• Application Number:
  US15/332,492
• Publication Number:
  US 20170226177A1
• Time in Patent Office: 953 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 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 method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 60% identical to GHRH 1-29, wherein the peptidomimetic macrocycle comprises at least two macrocycle-forming linkers, wherein the first of the at least two macrocycle-forming linkers connects a first amino acid to a second amino acid, and the second of the at least 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, wherein the peptidomimetic macrocycle comprises a helix.

2. The method of claim 1, wherein the amino acid sequence of the peptidomimetic macrocycle is at least about 60% identical to an amino acid sequence chosen from the group consisting of SEQ ID NO. 2-180.

3. The method 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 SEQ ID NO. 2-180.

4. The method 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 SEQ ID NO. 2-180.

5. The method of claim 1, wherein the amino acid sequence of said peptidomimetic macrocycle is chosen from the group consisting of SEQ ID NO. 2-180.

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

-helix.

7. The method of claim 1, wherein the condition is a cachexia.

8. The method of claim 1, wherein the condition is a lipodystrophy.

9. The method of claim 1, wherein the condition is a growth hormone disorder.

10. The method of claim 1, wherein each of the at least two 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;

or 25 and 29 of GHRH 1-29.

11. The method of claim 1, wherein each of the at least two 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;

or 21 and 28 of GHRH 1-29.

12. The method of claim 1, 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 of GHRH 1-29; and

the second macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acid 15 and 22;

18 and 25;

21 and 25;

21 and 28;

22 and 29;

or 25 and 29 of GHRH 1-29.

13. The method of claim 1, 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;

or 12 and 19 of GHRH 1-29; and

the second macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acid 15 and 22;

18 and 25;

21 and 25;

or 21 and 28 of GHRH 1-29.

14. The method of claim 1, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to amino acids locations 4 and 8 of GHRH 1-29.

15. The method of claim 1, wherein the second macrocycle-forming linker connects a pair of amino acids corresponding to amino acid locations 21 and 25 of GHRH 1-29.

16. The method of claim 1, 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.

17. The method of claim 1, wherein each amino acid connected by the at least two macrocycle-forming linkers is an α

,α

-disubstituted amino acid.

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

19. The method of claim 18, wherein L₁ and L₂ are independently alkylene, alkenylene or alkynylene.

20. The method of claim 18, wherein L₁ and L₂ are independently C₃-C₁₀ alkylene or alkenylene.

21. The method of claim 18, wherein L₁ and L₂ are independently C₃-C₆ alkylene or alkenylene.

22. The method of claim 18, wherein R₁ and R₂ are independently H.

23. The method of claim 18, wherein R₁ and R₂ are independently alkyl.

24. The method of claim 18, wherein R₁ and R₂ are independently methyl.

25. The method of claim 18, wherein one of R₁ and R₂ is —

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

26. The method of claim 18, wherein the sum of x+y+z is 2, 3, or 6.

27. The method of claim 18, wherein each of v and w is independently an integer from 1 to 25.

28. The method of claim 18, 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 GHRH 1-29.

29. The method of claim 18, wherein u is 2.

30. The method of claim 29, wherein the peptidomimetic macrocycle has the formula:

31. The method of claim 30, wherein the sum of x′

+y′

+z′

is 2, 3, or 6.

32. The method of claim 1, wherein the condition is a muscle wasting disease.

33. The method of claim 1, wherein the condition is a growth hormone deficiency.

34. The method of claim 1, wherein the condition is gastroparesis.

35. A method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises an amino acid sequence of formula:

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-X27-X28-X29 

 

(SEQ ID NO;

     1)

wherein;

X1 is Tyr or His;

X2 is Ala, D-Ala, or Val;

X3 is Asp;

X4 is Ala or a crosslinked amino acid;

X5 is Ile;

X6 is Phe;

X7 is Thr;

X8 is Gln, Asn, or a crosslinked amino acid;

X9 is Ser or a crosslinked amino acid;

X10 is Tyr;

X11 is Arg, Ala or Gln;

X12 is Lys, Ala, Gln or a crosslinked amino acid;

X13 is Val or Ile;

X14 is Leu;

X15 is Gly, Ala or a crosslinked amino acid;

X16 is Gln, Glu or a crosslinked amino acid;

X17 is Leu;

X18 is Ser, Tyr or a crosslinked amino acid;

X19 is Ala or a crosslinked amino acid;

X20 is Arg or Gln;

X21 is Lys, Gln or a crosslinked amino acid;

X22 is Leu, Ala, or a crosslinked amino acid;

X23 is Leu;

X24 is Gln, Glu or His;

X25 is Asp, Glu or a crosslinked amino acid;

X26 is Ile;

X27 is Met, Ile, Leu or Nle;

X28 is Ser or a crosslinked amino acid;

X29 is Arg, Ala, Gln or a crosslinked amino acid;

wherein at least one of the crosslinked amino acids is an α

,α

-disubstituted amino acid;

wherein the peptidomimetic macrocycle comprises at least one macrocycle-forming linker connecting at least one pair of amino acids selected from X1-X29;

L is a macrocycle-forming linker of the formula -L₁-L₂-;

L₁ and L₂ are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—

R₄—

K—

R₄-]_n, each being optionally substituted with R₅, wherein n is an integer from 1-5;

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

each K is O, S, SO, SO₂, CO, or CO₂;

each R₅ is independently halogen, alkyl, —

OR₆, —

N(R₆)₂, —

SR₆, —

SOR_E, —

SO₂R₆, —

CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent; and

each R₆ is independently —

H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent.

36. The method of claim 35, wherein the at least one 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;

or X25 and X29.

37. The method of claim 35, wherein the at least one 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;

or X21 and X28.

38. The method of claim 35, wherein the condition is a muscle wasting disease.

39. The method of claim 35, wherein the condition is a growth hormone deficiency.

40. The method of claim 35, wherein the condition is gastroparesis.

41. The method of claim 35, wherein the condition is a cachexia.

42. The method of claim 35, wherein the condition is a lipodystrophy.

43. The method of claim 35, wherein the condition is a growth hormone disorder.