Compounds and methods for modulating cell adhesion

• US 20060183884A1
• Filed: 12/09/2005
• Published: 08/17/2006
• Est. Priority Date: 07/12/1996
• Status: Abandoned Application

• Current Assignee: Adherex Technologies, Inc.
• Original Assignee: Adherex Technologies, Inc.
• Inventors: Ali, Anmar, George, Sarah Jane, Farookhi, Riaz, Blaschuk, Orest W., Gour, Barbara J.
• Application Number:
  US11/299,289
• Publication Number:
  US 20060183884A1
• Time in Patent Office: Days
• US Class Current: 530/317
• 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 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• 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

Cyclic peptides comprising a cadherin cell adhesion recognition sequence HAV, and compositions comprising such cyclic peptides, are provided. Methods for using such peptides for modulating cadherin-mediated cell adhesion in a variety of contexts are also provided.

Claims

1. A cyclic peptide having the formula:

2. A cyclic peptide according to claim 1, the peptide has an N-terminal acetyl, formyl or mesyl group.

3. A cyclic peptide according to claim 1, wherein X and Y are each independently selected from the group consisting of cysteine, penicillamine, β

,β

-tetramethylene cysteine, β

,β

-pentamethylene cysteine, β

-mercaptopropionic acid, β

,β

-pentamethylene-β

-mercaptopropionic acid, 2-mercaptobenzene, 2-mercaptoaniline and 2-mercaptoproline.

4. A cyclic peptide according to claim 1, wherein X and Y are cysteine residues.

5. A cyclic peptide according to claim 1, wherein the cyclic peptide comprises a sequence selected from the group consisting of:

N—

Ac-CHAVC-NH₂ (SEQ ID NO;

10), N—

Ac-CHAVC-Y—

NH₂ (SEQ ID NO;

84), N—

N—

Ac-CHAVDC-NH₂ (SEQ ID NO;

20), N—

Ac-CHAVDIC-NH₂ (SEQ ID NO;

50), N—

Ac-CHAVDINC-NH₂ (SEQ ID NO;

51), N—

Ac-CHAVDINGC-NH₂ (SEQ ID NO;

76), N—

Ac-CAHAVC-NH₂ (SEQ ID NO;

22), N—

Ac-CAHAVDC-NH₂ (SEQ ID NO;

26), N—

Ac-CAHAVDIC-NH₂ (SEQ ID NO;

24), N—

Ac-CRAHAVDC-NH₂ (SEQ ID NO;

28), N—

Ac-CLRAHAVC-NH₂ (SEQ ID NO;

30), N—

Ac-CLRAHAVDC-NH₂ (SEQ ID NO;

32), N—

Ac-CSHAVC-NH₂ (SEQ ID NO;

36), N—

Ac-CFSHAVC-NH₂ (SEQ ID NO;

85), N—

Ac-CLFSHAVC-NH₂ (SEQ ID NO;

_—

86), N—

Ac-CHAVSC-NH₂ (SEQ ID NO;

38), N—

Ac-CSHAVSC-NH₂ (SEQ ID NO;

40), N—

Ac-CSHAVSSC-NH₂ (SEQ ID NO;

42), N—

Ac-CHAVSSC-NH₂ (SEQ ID NO;

44), N—

Ac-KHAVD-NH₂ (SEQ ID NO;

12), N—

Ac-DHAVK-NH₂ (SEQ ID NO;

14), N—

Ac-KHAVE-NH₂ (SEQ ID NO;

16), N—

Ac-AHAVDI-NH₂ (SEQ ID NO;

34), N—

Ac-SHAVDSS-NH₂ (SEQ ID NO;

77), N—

Ac-KSHAVSSD-NH₂ (SEQ ID NO;

48), N—

Ac-CHAVC-S—

NH₂ (SEQ ID NO;

87), N—

Ac—

S-CHAVC-NH₂ (SEQ ID NO;

88), N—

Ac-CHAVC-SS—

NH₂ (SEQ ID NO;

89), N—

Ac—

S-CHAVC-S—

NH₂ (SEQ ID NO;

90), N—

Ac-CHAVC-T-NH₂ (SEQ ID NO;

91), N—

Ac-CHAVC-E-NH₂ (SEQ ID NO;

92), N—

Ac-CHAVC-D-NH₂ (SEQ ID NO;

93), N—

Ac-CHAVYC-NH₂ (SEQ ID NO;

94), CH₃—

SO₂-HN-CHAVC-Y—

NH₂ (SEQ ID NO;

95), CH₃—

SO₂—

HN-CHAVC-NH₂ (SEQ ID NO;

96), HC(O)—

NH-CHAVC-NH₂ (SEQ ID NO;

96), N—

Ac-CHAVPen-NH₂ (SEQ ID NO;

97), N—

Ac-PenHAVC-NH₂ (SEQ ID NO;

98) and N—

Ac-CHAVPC-NH₂. (SEQ ID NO;

99).

6. A cyclic peptide according to claim 5, wherein the cyclic peptide has an N-terminal acetyl group or CH₃—

SO₂—

group, and a C-terminal amide group.

8. A cell adhesion modulating agent comprising a cyclic peptide according to any one of claims 1-7.

34. A method for modulating vascular smooth muscle cell migration, comprising contacting a vascular smooth muscle cell with a cell adhesion modulating agent according to claim 8, and thereby modulating vascular smooth muscle cell migration.

35. A method for modulating vascular smooth muscle cell apoptosis, comprising contacting a vascular smooth muscle cell with a cell adhesion modulating agent according to claim 8, and thereby modulating vascular smooth muscle cell apoptosis.

36. A method for preventing the formation or advance of restenosis, comprising contacting a cadherin expressing cell with a cell adhesion modulating agent according to claim 8, and thereby preventing the formation or advance of restenosis.

37. A method for maintaining vessel luminal area following vascular trauma, comprising contacting a cadherin expressing cell with a cell adhesion modulating agent according to claim 8, and thereby maintaining vessel luminal area following vascular trauma.

38. A method for treating a traumatized vessel, comprising contacting a cadherin expressing cell with a cell adhesion modulating agent according to claim 8, and thereby treating a traumatized vessel.

52. A method for the modulation of bone adhesion, comprising contacting a cadherin-expressing cell with a modulating agent according to claim 8, and thereby modulating bone adhesion.

53. An implantable medical device or material linked to, coated with or having interspersed within, a cell adhesion modulating agent according to claim 8.

54. The medical device of claim 53, wherein the medical device is selected from the group consisting of a balloon, stent, shunt, catheter, stent graft, vascular graft, vascular patch, filter, adventitial wrap, intraluminal paving system, cerebral stent, cerebral aneurysm filter coil, myocardical plug, pacemaker lead, dialysis access graft, and heart valve.

7. A cyclic peptide comprising a dimer or multimer of the sequence His-Ala-Val.

9-33. -33. (canceled)

39-51. -51. (canceled)