Methods of treating conditions associated with an EDG-4 receptor

• US 20050113283A1
• Filed: 03/14/2003
• Published: 05/26/2005
• Est. Priority Date: 01/18/2002
• Status: Abandoned Application

• Current Assignee: Maniv Energy Capital
• Original Assignee: Maniv Energy Capital
• Inventors: Spencer, Juliet, Gluchowski, Charles, Solow-Cordero, David, Shankar, Geetha
• Application Number:
  US10/390,429
• Publication Number:
  US 20050113283A1
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495

Abstract

The present invention provides a method of modulating an Edg-4 receptor mediated biological activity in a cell. A cell expressing the Edg-4 receptor is contacted with a modulator of an Edg-4 receptor sufficient to modulate the Edg-4 receptor mediated biological activity. In another aspect, the present invention provides a method for modulating an Edg-4 receptor mediated biological activity in a subject. A therapeutically effective amount of a modulator of the Edg-4 receptor is administered to the subject.

Claims

1. A method of modulating an Edg-4 receptor mediated biological activity comprising contacting a cell expressing the Edg4 receptor with an amount of a modulator of the Edg-4 receptor sufficient to modulate the Edg4 receptor mediated biological activity wherein the modulator is not a phospholipid.

2. A method of modulating an Edg4 receptor mediated biological activity in a subject comprising administering to the subject a therapeutically effective amount of a modulator of the Edg-4 receptor wherein the modulator is not a phospholipid.

3. The method of claim 1 or 2, wherein the modulator is an agonist.

4. The method of claim 1 or 2, wherein the modulator is an antagonist.

5. The method of claim 1 or 2, wherein the modulator exhibits at least about 200 fold inhibitor selectivity for Edg4 relative to other Edg receptors.

6. The method of claim 1 or 2, wherein the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.

7. The method of claim 1 or 2, wherein the modulator exhibits at least about 200 fold inhibitory selectivity for Edg4 relative to Edg-2 and Edg-7 receptors.

8. The method of claim 1 or 2, wherein the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.

9. The method of claim 1 or 2, wherein the biological activity is cell proliferation.

10. The method of claim 9, wherein the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.

11. The method of claim 9, wherein the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.

12. The method of claim 9, wherein the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-4 relative to Edg2 and Edg-7 receptors.

13. The method of claim 9, wherein the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.

14. The method of claim 9, wherein cell proliferation leads to ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colon cancer or prostrate cancer.

15. The method of claim 9, wherein cell proliferation is stimulated by LPA.

16. The method of claim 1 or 2, wherein the biological activity is calcium mobilization, VEGP synthesis, IL-8 synthesis, platelet activation, cell migration, phosphoinositide hydrolysis, inhibition of cAMP formation, increasing the level of fatty acids, actin polymerization, apoptosis, angiogenesis, inhibition of wound healing, inflammation, expression of endogenous protein growth factors, cancer invasiveness, regulation of autoimmunity or atherogenesis.

17. The method of claim 1 or 2 wherein the modulator binds to the Edg-4 receptor with a binding constant of at least about 1 μ

M.

18. The method of claim 1 or 2 wherein the modulator binds to the Edg-4 receptor with a binding constant between about 1 μ

M and 100 nM.

19. The method of claim 1 or 2, wherein the modulator is a nucleic acid, peptide or carbohydrate.

20. The method of claim 1 or 2, wherein the modulator is an organic molecule of molecular weight of less than 750 daltons.

21. The method of claim 1, wherein the cell is a HTC hepatoma cell, an ovarian cell, an epithelial cell, a fibroblast cell, a neuronal cell, a Xenopus laevis oocyte cell, a carcinoma cell, a pheochromocytoma cell, a myoblast cell, a platelet cell or a fibrosarcoma cell.

22. The method of claim 21, wherein the cell is OV202 human ovarian cell, a HTC rat hepatoma cell, SKOV3 and CAOV-3 human ovarian cancer cells, MDA-MB-453 breast cancer cell, MDA-MB-23 1 breast cancer cell, HUVEC cells A43 1 human epitheloid carcinoma cell or a HT-1 080 human fibrosarcoma cell.

23. The method of claim 1 or 2, wherein the modulator is a compound of stuctural formula (I):

24. The method of claim 23, wherein R₁ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyloxy or substituted sulfonylamino.

25. The method of claim 23, wherein R₁ is substituted alkyl.

26. The method of claim 23, wherein R₁ is substituted haloalkyl.

27. The method of claim 23, wherein R₁ is substituted trifluoroalkyl.

28. The method of claim 23, wherein R₁ has the structural formula (II):

29. The method of claim 28, wherein R₃ is fluoroalkyl, R₄ is oxo and R₅ and R₆ are independently hydrogen, halo or alkyl.

30. The method of claim 28, wherein R₃ is trifluoromethyl, R₄ is oxo and R₅ and R₆ are independently hydrogen, chloro or methyl.

31. The method of claim 28, wherein R₅ and R₆ are hydrogen.

32. The method of claim 28 wherein R₅ is hydrogen and R₆ is chloro or methyl.

33. The method of claim 23, wherein X is 0, A is NR₂ and R₂ is hydrogen.

34. The method of claim 23, wherein B and C are independently, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

35. The method of claim 23, wherein B and C are independently indolo, substituted indolo, imidazolo, substituted, imidazolo, pyrazolo, substituted pyrazolo, phenyl or substituted phenyl.

36. The method of claim 23, wherein B is heteroaryl or substituted heteroaryl and C is aryl or substituted aryl.

37. The method of claim 23, wherein B is pyrazolo or substituted pyrazolo and C is phenyl or substituted phenyl.

38. The method of claim 23, wherein the modulator is a compound of structural formula (III);

39. The method of claim 23, wherein the modulator is compound of the formula:

40. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (IV):

41. The method of claim 40, wherein the modulator is a compound of the following formula:

42. The method of claim 1 or 2, herein the modulator is a compound of structural formula (V):

43. The method of claim 42, wherein R₁ and R₂ are independently aryl, substituted aryl, heteroaryl or substituted heteroaryl.

44. The method of claim 42, wherein R₂ is indole and R₃ and R₄ are hydrogen.

45. The method of claim 42, wherein the modulator is a compound of the following formula:

46. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (V):

47. The method of claim 46, wherein R₁ and R₂ together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.

48. The Method of claim 46, wherein:

R₁ and R₂ together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring; and

R₃ and R₄ together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.

49. The method of claim 46, wherein:

R₁ and R₂ together form a 6-membered substituted or unsubstituted cyclic or aromatic ring; and

R₃ and R₄ together form a 6-membered substituted or unsubstituted cyclic or aromatic ring.

50. The method of claim 46, wherein:

R₁ and R₂ form a 6-membered substituted cyclic or aromatic ring, and R₃ and R₄ form a 6-membered substituted cyclic or aromatic ring.

51. The method of claim 46, wherein the modulator is a compound of the following formula:

52. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (VII):

53. The method of claim 52, wherein the modulator is a compound of the following formula:

54. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (VIII):

55. The method of claim 54, wherein R₇ is substituted or unsubstituted aryl.

56. The method of claim 54, wherein the modulator is a compound of the following formula:

57. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (IX):

58. The method of claim 57, wherein R₂ is a substituted alkyl, and one or more of R₅, R₇, R₈, R₉ and R₁₀ are halos.

59. The method of claim 57, wherein R₂ is a halo-substituted alkyl.

60. The method of claim 57, wherein R₂ is —

CF₃.

61. The method of claim 57, wherein the modulator is a compound of the following formula:

62. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (X):

63. The method of claim 62, wherein R₃ and R₇ are substituted or unsubstituted aryls.

64. The method of claim 62, wherein the modulator is a compound of the following formula:

65. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (XI):

66. The method of claim 65, wherein R₂ and R₃ together form a 5-membered ring.

67. The method of claim 65, wherein R₂ and R₃ together form a 5-membered ring, and R₇ and R₈ together form a 5-membered ring.

68. The method of claim 65, wherein the modulator is a compound of the following formula:

69. The method of claim 65, wherein R₂ is a substituted or unsubstituted pipeline moiety.

70. The method of claim 65, wherein the modulator is a compound of the following formula:

71. The method of claim 1 or 2, wherein the modulator is a compound of structural formula (XII):

72. The method of claim 71, wherein the modulator is a compound of the following formula:

73. A method for treating or preventing cancers, acute lung diseases, acute inflammatory exacerbation of chronic lung diseases, surface epithelial cell injury, or cardiovascular diseases in a patient comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of structural formula (I)-(XII).

74. A method for treating or preventing ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer, prostrate cancer, adult respiratory distress syndrome (ARDS), asthma, transcomcal freezing, cutaneous burns, ischemia or arthesclerosis in a patient comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of structural formula (I)-(XII).

75. A method for treating or preventing cancers, acute lung diseases, acute inflammatory exacerbation of chronic lung diseases, surface epithelial cell injury, or cardiovascular diseases in a patient comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of structural formula (I)-(XII) and one or more agonists or antagonists of an LPA receptor.

76. A method for treating or preventing cancers, acute lung diseases, acute inflammatory exacerbation of chronic lung diseases, surface epithelial cell injury, or cardiovascular diseases in a patient comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of structural formula (I)-(XII) and one or more drugs useful in treating or preventing cancers, acute lung diseases, acute inflammatory exacerbation of chronic lung diseases, surface epithelial cell injury, or cardiovascular diseases.