Cyclic peptides and analogs useful to treat allergies

• US 20030166138A1
• Filed: 07/16/2002
• Published: 09/04/2003
• Est. Priority Date: 02/21/2002
• Status: Abandoned Application

• Current Assignee: Rigel Pharmaceuticals, Inc.
• Original Assignee: Rigel Pharmaceuticals, Inc.
• Inventors: Anderson, Dave, Kinsella, Todd, Ohashi, Cara
• Application Number:
  US10/197,927
• Publication Number:
  US 20030166138A1
• Time in Patent Office: Days
• US Class Current: 435/69.1
• 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: C07K 5/126 Tetrapeptides
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

The present provides cyclic compounds capable of modulating IgE production, as well as IL-4 induced processes associated therewith, and methods of using the cyclic compounds in a variety of in vitro and in vitro contexts.

Claims

1. A cyclic compound composed of from 4 to 10 residues comprising a contiguous sequence of residues selected from structures (Ia)-(Ie):

X²⁶˜

X²⁵˜

X²¹˜

X²⁵;

 

 

(Ia) X²²˜

X²⁴˜

X²⁷˜

X²⁹;

 

 

(Ib) X²¹˜

X²²˜

X²⁴˜

X²⁹;

 

 

(Ic) X²²˜

X²¹˜

X²¹˜

X²⁹;

 

 

(Id) X²⁸˜

Glu˜

X²¹˜

X^29;

and 

 

(Ie)

pharmaceutically acceptable salt thereof, wherein;

each X²¹ is independently a small residue;

each X²² is independently a basic residue;

each X²⁴ is independently a hydrophobic residue;

each X²⁵ is independently an aromatic residue;

each X²⁶ is independently a polar residue;

each X²⁷ is independently a small or a cysteine-like residue;

each X²⁸ is independently a small or an acidic residue; and

each X²⁹ is independently any residue; and

each “

˜

”

independently represents an amide, a substituted amide, an isostere of an amide or an amide or peptido mimetic linkage.

2. The cyclic compound of claim 1 which is selected from the group consisting of structures (IIa)-(IIe):

cyclo(X²⁶˜

X²⁵˜

X²¹˜

X²⁵˜

X³⁰˜

X³⁰˜

X³⁰) 

 

(IIa) cyclo(X²²˜

X²⁴˜

X²⁷˜

X²⁹˜

X³⁰˜

X³⁰˜

X³⁰) 

 

(IIb) cyclo(X²¹˜

X²²˜

X²⁴˜

X²⁹˜

X³⁰˜

X³⁰˜

X³⁰) 

 

(IIc) cyclo(X²²˜

X²¹˜

X²¹˜

X²⁹˜

X³⁰˜

X³⁰˜

X³⁰) 

 

(IId) cyclo(X²⁸˜

Glu˜

X²¹˜

X²⁹˜

X³⁰˜

X³⁰˜

X³⁰); and

 

 

(IIe)

pharmaceutically acceptable salts thereof, wherein;

X²¹X²²X²³X²⁴X²⁵X²⁶X²⁷X²⁸X²⁹ and “

˜

”

are as defined for claim 1 and each X³⁰ is independently present or absent, and if present, is any residue.

3. The cyclic compound of claim 2 which is structure (IIa).

4. The cyclic compound of claim 3 in which:

each X²¹ is independently selected from the group consisting of a Ser, a Thr, a Cys and a Asn residue; and

/or

each X²⁵ is independently selected from the group consisting of a Trp, a Phe, a Tyr and a His residue.

5. The cyclic compound of claim 3 which has the structure (IIá

)

cyclo (X⁴⁰˜

X⁴¹˜

X⁴²˜

X⁴³˜

X³⁰X³⁰ X³⁰) 

 

(IIá

)

wherein;

X³⁰ is as defined in claim 3;

X⁴⁰ is a Ser, a Thr, a Cys or a Asn residue;

X⁴¹ is a Trp, a Phe, a Tyr or a His residue;

X⁴² is a Ser or a Thr residue; and

X⁴³ is a Phe, a Tyr, a His or a Trp residue.

6. The cyclic compound of claim 5 which is composed of 5, 6 or 7 residues.

7. The cyclic compound of claim 5 in which X³⁰˜

X³⁰˜

X³⁰ is selected from the group consisting of (a Phe residue)˜

(a Thr residue)˜

(a Ser residue), (a Ser residue)˜

(an Arg residue), a Ser residue and a Val residue.

8. The cyclic compound of claim 5 which is selected from the group consisting of cyclo(TWSFV) cyclo(SEQ ID NO:

1), cyclo(CWSYFTS) cyclo(SEQ ID NO;

5), cyclo(NWSHSR) cyclo(SEQ ID NO;

9), cyclo(NFTFS) cyclo(SEQ ID NO;

10) and retro and retro-inverso peptides thereof.

9. The cyclic compound of claim 2 which is structure (IIb).

10. The cyclic compound of claim 9 which is composed of 5, 6 or 7 residues.

11. The cyclic compound of claim 9 in which:

X²² is an Arg, a Lys or an Orn residue;

X²⁴ is an aromatic residue or a small aliphatic residue; and

/or

X²⁷ is a small hydroxyl-containing or a Cys residue.

12. The cyclic peptide of claim 9 in which X²⁹˜

X³⁰˜

X³⁰˜

X³⁰ is selected from the group consisting of (hydroxyl-containing residue)˜

(aliphatic residue), (aliphatic residue)˜

(Asn residue), (basic residue)˜

(basic residue)˜

(acidic residue) and (sulfanyl-containing residue)˜

(basic aromatic residue)˜

(small hydroxyl-containing residue)˜

(basic residue).

13. The cyclic peptide of claim 8 which is selected from the group consisting of cyclo(RWSSL) cyclo(SEQ ID NO:

6), cyclo(RISLN) cyclo(SEQ ID No;

4), cyclo(RISRRD) cyclo(SEQ ID NO;

15) and retro and retro-inverso peptides thereof.

14. The cyclic compound of claim 2 which is structure (IIc).

15. The cyclic compound of claim 14 which is composed of 5 residues.

16. The cyclic compound of claim 14 in which X²⁹˜

X³⁰˜

X³⁰˜

X³⁰ is selected from the group consisting of (aliphatic residue)(acidic residue) and (aliphatic residue)(hydroxyl-containing residue).

17. The cyclic compound of claim 16 in which:

X²¹ is small hydroxyl-containing residue or a small aliphatic residue;

X²² is an Arg, a Lys or an Orn residue; and

/or

X²⁴ is a small aliphatic residue or a hydrophobic residue.

18. The cyclic compound of claim 14 which is selected from the group consisting of cyclo(SRVEI) cyclo(SEQ ID NO:

2), cyclo(ARFVS) cyclo(SEQ ID NO;

3) and retro and retro-inverso peptides thereof.

19. The cyclic compound of claim 2 which is structure (IId).

20. The cyclic compound of claim 19 which is composed of 5 residues.

21. The cyclic compound of claim 20 in which X²⁹˜

X³⁰˜

X³⁰˜

X³⁰ is selected from the group consisting of (aromatic residue)˜

(small residue), (small residue)˜

(structurally constrained residue), and (small hydroxyl- or sulfanyl-containing residue)˜

(Met residue).

22. The cyclic compound of claim 21 in which:

X²² is an Arg residue; and

/or

each X²¹ is independently a small hydroxyl-containing residue.

23. The cyclic compound of claim 19 which is selected from the group consisting of cyclo(RSSFG) cyclo(SEQ ID NO:

7), cyclo(RSTGP) cyclo(SEQ ID NO;

16) and retro and retro-inverso peptides thereof.

24. The cyclic compound of claim 2 which is structure (IIe).

25. The cyclic compound of claim 24 which has the structure (IIe′

);

cyclo(X⁵⁰˜

Glu˜

X⁵¹˜

X²⁹X³⁰˜

X³⁰˜

X³⁰) 

 

(IIe′

)

wherein;

X²⁹ and X³⁰ are as defined in claim 2;

X⁵⁰ is a Glu, a Ser or an Ala residue; and

/or

X⁵¹ is a Ser or an Ala residue.

26. The cyclic compound of claim 24 or 25 which is composed of 5 residues.

27. The cyclic compound of claim 26 in which X²⁹˜

X³⁰˜

X³⁰˜

X³⁰ is selected from the group consisting of aromatic residue, (aliphatic residue)˜

(aliphatic residue), (small hydroxyl-containing residue)˜

(aromatic residue) and (small acidic residue)˜

(aromatic residue).

28. The cyclic compound of claim 24 which is selected from the group consisting of cyclo(EQSVI) cyclo(SEQ ID NO:

13), cyclo(SQSY) cyclo(SEQ ID NO;

14), cyclo(AQASW) cyclo(SEQ ID NO;

19) and retro and retro-inverso peptides thereof.

29. The cyclic compound of claim 1 which is selected from the group consisting of:

cyclo(X¹⁶˜

X⁵˜

X¹⁸˜

X¹⁷˜

X¹⁹);

cyclo(X¹⁶˜

X¹⁵˜

X¹⁸˜

X⁴˜

X⁸);

cyclo(X¹⁶˜

X¹˜

X¹⁵˜

X⁵˜

X¹⁸);

cyclo(X¹⁶˜

X¹⁰˜

X¹²˜

X¹⁵˜

X⁸);

cyclo(X¹⁶˜

X²⁰˜

X⁵˜

X¹⁷˜

X¹⁶˜

X²˜

X¹⁹);

cyclo(X¹⁶˜

X¹⁶˜

X¹⁰˜

X¹⁵˜

X¹⁹);

cyclo(X¹⁶˜

X⁵˜

X⁶˜

X¹⁵˜

X¹⁶);

cyclo(X¹⁶˜

X⁴˜

X¹¹˜

X⁵˜

X¹⁶˜

X⁸˜

X¹⁹);

cyclo(X¹⁶˜

X⁴˜

X¹¹˜

X⁵˜

X¹⁶˜

X⁷);

cyclo(X¹⁶˜

X¹²˜

X⁵˜

X¹⁷˜

X⁵);

cyclo(X¹⁶˜

X¹²˜

X⁸˜

X¹³˜

X¹⁴);

cyclo(X¹⁶˜

X⁶˜

X¹˜

X³˜

X¹⁶);

cyclo(X¹⁶˜

X¹⁸˜

X⁸˜

X⁴˜

X¹⁴);

cyclo(X¹⁶˜

X²⁰˜

X¹⁶˜

X¹⁴);

cyclo(X¹⁶˜

X¹⁵˜

X¹⁵˜

X³˜

X¹⁵˜

X⁸);

cyclo(X¹⁶˜

X¹⁷˜

X⁶˜

X¹³ ˜

X¹⁵);

cyclo(X¹⁶˜

X¹⁸˜

X¹⁸˜

X¹⁷˜

X¹⁵);

cyclo(X¹⁶˜

X¹³˜

X¹⁹˜

X⁹˜

X¹⁰˜

X¹⁸˜

X⁶);

cyclo(X¹⁶˜

X¹⁶˜

X¹˜

X¹⁴˜

X¹); and

cyclo(X¹⁶˜

X³˜

X⁷˜

X¹⁶˜

X¹⁴);

wherein;

X¹ is an Ala residue;

X² is a Cys residue;

X³ is an Asp residue;

X⁴ is a Glu residue;

X⁵ is a Phe residue;

X⁶ is a Gly residue;

X⁷ is a His residue;

X⁸ is an Ile residue;

X⁹ is a Lys residue;

X¹⁰ is a Leu residue;

X¹¹ is a Met residue;

X¹² is an Asn residue;

X¹³ is a Pro residue;

X¹⁴ is a Glu residue;

X¹⁵ is an Arg residue;

X¹⁶ is a Ser residue;

X¹⁷ is a Thr residue;

X¹⁸ is a Val residue;

X¹⁹ is a Trp residue;

X²⁰ is a Tyr residue; and

retro- and retro-inverso analogs thereof.

30. The cyclic compound of claim 1 or claim 29 in which all residues having a chiral α

-carbon are in the same configuration about the α

-carbon.

31. The cyclic compounds of claim 30 in which all residues having a chiral α

-carbon are in the L-configuration about the α

-carbon.

32. The cyclic compounds of claim 1, 2 or 30 which are peptides.

33. The cyclic compounds of claim 32 which are composed wholly of gene-encoded amino acids.

34. The cyclic compounds of claim 1, 2 or 30 which are peptide analogs.

35. The cyclic compounds of claim 34 which have enhanced in vivo stability compared to a corresponding cyclic peptide composed wholly of gene-encoded amino acids.

36. The cyclic compounds of claim 1, 2 or 30 which are labeled.

37. The cyclic compounds of claim 1, 2 or 3 which include a moiety that enhances transport across a membrane.

38. The cyclic compounds of claim 1, 2 or 30 which inhibit at least about 25% of IL-4 induced transcription of a germline ε

promoter as compared to control cells.

39. A polynucleotide capable of expressing a cyclic peptide comprising a first segment encoding a C-terminal intein domain, a second segment encoding a linear version of cyclic compound according to claim 33 and a third segment encoding an N-terminal intein domain, wherein the first second and third segments are arranged such that the polynucleotide expresses a cyclic peptide.

40. The polynucleotide of claim 39 which further includes a promoter upstream of the encoding segments.

41. The polynucleotide of claim 35 in which the second segment encodes a peptide selected from the group consisting of:

42. A host cell or progeny thereof comprising a polynucleotide according to claim 39.

43. A pharmaceutical composition comprising a cyclic compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.

44. A method of inhibiting IgE production in a B-cell, or a process associated therewith, comprising administering to the cell a compound according to claim 1.

45. The method of claim 44 in which the process inhibited is IL-4 induced germline ε

transcription.

46. The method of claim 44 in which the process inhibited is IL-4 induced isotype switching to produce IgE.

47. The method of claim 44 in which the cyclic compound is administered to the cell via the polynucleotide of claim 39.

48. A method of treating or preventing a disease associated with, caused by or mediated by IgE production and/or accumulation, or symptoms associated therewith, comprising administering to an animal suffering from such a disease an amount of a cyclic compound according to claim 1 effective to treat or prevent the disease or its associated symptoms.

49. The method of claim 48 in which the disease is selected from the group consisting of an anaphylactic or hypersensitivity reaction, atopic dermatitis, atopic eczema, atopic asthma, allergic rhinitis, allergic conjunctivitis, systemic mastocytosis, hyper IgE syndrome, IgE gammopathies and B-cell lymphoma.

50. The method of claim 48 in which the cyclic compound administered is a compound according to claim 32.

51. The method of claim 48 in which the cyclic compound is administered via administration of a polynucleotide capable of expressing the cyclic compound in the animal.

52. The method of claim 48 in which the animal is a human.