Channel modulators

• US 10,465,188 B2
• Filed: 08/21/2015
• Issued: 11/05/2019
• Est. Priority Date: 08/22/2014
• Status: Active Grant

• Current Assignee: OcuNexus Therapeutics, Inc.
• Original Assignee: Auckland UniServices Limited (Auckland University)
• Inventors: Green, Colin Richard, Kim, Yeri, Phillips, Anthony, Duft, Bradford James
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US14/833,041
• Publication Number:
  US 20160177298A1
• Time in Patent Office: 1,537 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/382 having six-membered rings, e.g. thioxanthenes thiothixene A61K31/496
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/3231 : having an additional ring, e.g. LNA, ENA

Abstract

The inventions relate to compositions and articles of manufacture comprising connexin modulators, pannexin modulators, gap junction modulators, hemichannel modulators, and pannexin channel modulators and their use, alone or in combination, in treating ocular and other disorders.

Claims

1. A method for treating a subject for an ocular disorder selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, ocular fibrosis, retinal perfusion impairment, geographic atrophy, ocular inflammation, ocular vessel leak, ocular edema and ocular hypoxia, comprising administering to said subject a therapeutically effective amount of a small molecule connexin 43 hemichannel modulator, wherein said modulator is a compound according to Formula I:

3. The method of claim 1, wherein the age-related macular degeneration is wet age-related macular degeneration.

4. The method of claim 1, wherein the small molecule connexin 43 hemichannel modulator prevents, inhibits, and/or reduces connexin 43 hemichannel activity.

5. The method of claim 3, wherein choriocapillaris endothelial cell loss and/or choriocapillaris dropout is reduced.

6. The method of claim 3, wherein choroid inflammation is reduced.

7. The method of either of claim 3 or claim 4, wherein choriocapillaris endothelial cell loss is slowed or prevented.

9. The method of any one of claim 1, 2, 3, 4 or 8, wherein said small molecule connexin 43 hemichannel modulator is administered by topical, systemic, parenteral, intraocular, intravitreal, subconjunctival, or periocular administration.

10. The method of any one of claim 1, 2, 3, 4 or 8, wherein the small molecule connexin 43 hemichannel modulator is administered orally.

11. The method of one of claim 1, 2, 3, 4 or 8 wherein the subject is a human.

12. The method of any of claim 1, 2, 3, 4 or 8, wherein the small molecule connexin 43 hemichannel modulator is a compound according to Formula I.

13. The method of any of claim 1, 2, 3, 4 or 8, wherein the small molecule connexin 43 hemichannel modulator is a compound according to Formula II.

14. The method of any of claim 1, 2, 3, 4 or 8 wherein the small molecule connexin 43 hemichannel modulator is tonabersat.

15. The method of claim 12, wherein said small molecule connexin 43 hemichannel modulator is administered by oral, systemic, parenteral, or ocular administration.

16. The method of claim 14, wherein the small molecule connexin 43 hemichannel modulator is administered by oral, systemic, parenteral, or ocular administration.

17. The method of claim 15 wherein the small molecule connexin 43 hemichannel modulator is formulated for systemic administration.

18. The method of claim 17 wherein the small molecule connexin 43 hemichannel modulator is formulated for oral administration.

21. The method of claim 1, wherein inflammasome activity is reduced.

33. The method of claim 13, wherein said small molecule connexin 43 hemichannel modulator is administered by oral, systemic, parenteral, or ocular administration.

34. The method of claim 33, wherein the connexin modulator is administered orally.

35. The method of claim 13, wherein said connexin modulator is administered by oral, systemic, parenteral, or ocular administration.

36. The method of claim 35, wherein the connexin modulator is administered orally.

37. The method of claim 14 wherein the small molecule connexin 43 hemichannel modulator is formulated for systemic administration.

38. The method of claim 37 wherein the small molecule connexin 43 hemichannel modulator is formulated for oral administration.

41. The method of any of claim 1, 2, 3, 4 or 8, wherein the small molecule connexin 43 hemichannel modulator prevents, inhibits and/or reduces unwanted connexin 43 hemichannel opening.

45. The method of one of claim 21 to 29 or 30, wherein the subject is a human.

60. The method of claim 1, wherein the ocular disorder is age-related macular degeneration and the small molecule connexin 43 hemichannel modulator is tonabersat.

61. The method of claim 60, wherein the ocular disorder is wet age-related macular degeneration.

62. The method of claim 1, wherein the ocular disorder is diabetic retinopathy and the small molecule connexin 43 hemichannel modulator is tonabersat.

63. The method of claim 1, wherein the ocular disorder is macular edema and the small molecule connexin 43 hemichannel modulator is tonabersat.

64. The method of claim 63, wherein the macular edema is diabetic macular edema.

65. The method of claim 1, wherein the ocular disorder is retinal perfusion impairment and the small molecule connexin 43 hemichannel modulator is tonabersat.

66. The method of claim 1, wherein the ocular disorder is geographic atrophy and the small molecule connexin 43 hemichannel modulator is tonabersat.

67. The method of claim 1, wherein the ocular disorder is ocular vessel leak and the small molecule connexin 43 hemichannel modulator is tonabersat.

68. The method of claim 1, wherein the ocular disorder is ocular edema and the small molecule connexin 43 hemichannel modulator is tonabersat.

69. The method of claim 1, wherein the ocular disorder is ocular hypoxia and the small molecule connexin 43 hemichannel modulator is tonabersat.

73. The method of any of claim 60-71 or 72, wherein the subject is a human.

2. A method for treating a subject for inflammation of the choroid or the inner retina, comprising administering to said subject a therapeutically effective amount of a small molecule connexin 43 hemichannel modulator, wherein said modulator is a compound according to Formula I or Formula II and inflammation in the choroid or inner retina is reduced:

8. A method for treating a subject for retinal artery occlusion or central retinal vein occlusion, comprising administering a therapeutically effective amount of a small molecule connexin 43 hemichannel modulator to the eye of said subject, wherein said modulator is a compound according to Formula I or Formula II and said retinal artery occlusion or central retinal vein occlusion:

19. A method for treating a subject for age-related macular degeneration, clinical geographic atrophy, chronic macular ischemia, idiopathic polypoidal choroidopathy, diabetic maculopathy, diabetic retinopathy, hypertensive retinopathy, choroidal neovascularization, inflammatory choroidal neovascularization, central serous chorioretinopathy, macular telangiectasia, pattern dystrophy, subretinal neovascularization, ocular hemorrhages including subretinal pigment epithelial, subretinal, intraretinal or pre-retinal hemorrhages, retinal fibrosis, retinopathy of prematurity, or retinal hypoxia, comprising administering a therapeutically effective amount of a small molecule connexin 43 hemichannel modulator, wherein the small molecule connexin 43 hemichannel blocker is a compound according to Formula I or Formula II:

20. The method of claim 19 wherein the connexin modulator is tonabersat.

39. The method of claim 19 or 20 wherein the small molecule connexin 43 hemichannel modulator is formulated for oral, systemic, parenteral, or ocular administration.

40. The method of claim 39 wherein the small molecule connexin 43 hemichannel modulator is formulated for oral administration.

42. The method of claim 19, wherein the small molecule connexin 43 hemichannel modulator prevents, inhibits and/or reduces unwanted connexin 43 hemichannel opening.

43. The method of claim 20, wherein the small molecule connexin 43 hemichannel modulator prevents, inhibits and/or reduces unwanted connexin 43 hemichannel opening.

44. The method of one of claim 19 or 20, wherein the subject is a human.

70. The method of claim 19, wherein the ocular disorder is retinal hypoxia and the small molecule connexin 43 hemichannel modulator is tonabersat.

22. A method for treating leakage from and/or breakdown of blood vessels in the eye of a subject, comprising administering a therapeutically effective amount of a small molecule connexin 43 hemichannel modulator to said subject, wherein said modulator is a compound according to Formula I or Formula II and said blood vessel leak or breakdown is reduced:

23. A method according to claim 22, wherein the small molecule connexin 43 hemichannel modulator is a compound according to Formula I.

24. A method according to claim 22, wherein the small molecule connexin 43 hemichannel modulator is a compound according to Formula II.

25. A method according to claim 22, wherein the small molecule connexin 43 hemichannel modulator is tonabersat.

26. A method according to claim 22, wherein the subject has age-related macular degeneration.

27. A method according to claim 26, wherein the subject has wet age-related macular degeneration.

28. A method according to claim 22, wherein the subject has diabetic retinopathy.

29. A method according to claim 22, wherein the subject has diabetic macular edema.

30. A method according to claim 22, wherein the subject has impaired retinal perfusion.

31. A method according to any one of claim 22 to 29 or 30, wherein the small molecule connexin 43 hemichannel modulator is administered by oral, systemic, parenteral, or ocular administration.

32. The method of claim 31, wherein said small molecule connexin 43 hemichannel modulator is administered orally.

71. The method of claim 22, wherein the method is a method of treating blood vessel breakdown in the eye of a subject, and the small molecule connexin 43 hemichannel modulator is tonabersat.

72. The method of claim 22, wherein the method is a method of treating blood vessel leakage in the eye of a subject, and the small molecule connexin 43 hemichannel modulator is tonabersat.

74. The method of any of claim 26-29 or 30, wherein the small molecule connexin 43 hemichannel modulator is tonabersat.

75. The method of claim 74, wherein the subject is a human.

46. A method for treating a subject for an ocular disorder selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, ocular fibrosis, retinal perfusion impairment, geographic atrophy, ocular inflammation, ocular vessel leak, ocular edema and ocular hypoxia, comprising administering to said subject a small molecule connexin 43 hemichannel modulator in an amount effective to modulate inflammasome activity, wherein said modulator is a compound according to Formula I or Formula II and said ocular disorder is treated:

47. A method according to claim 46, wherein said inflammasome is the NLRP3 inflammasome.

48. A method according to claim 46 or claim 47, wherein said small molecule connexin 43 hemichannel modulator is administered by oral, systemic, parenteral, or ocular administration.

49. The method of claim 46 or claim 47, wherein the connexin modulator is administered orally.

50. The method of claim 48, wherein the subject is a human.

51. The method of claim 49, wherein the subject is a human.

52. The method of claim 46 or claim 47, wherein the connexin 43 modulator is tonabersat.

53. The method of claim 52, wherein tonabersat is administered orally.

54. A method for treating a subject for an ocular disorder characterized in whole or in part by retinal ganglion cell loss, comprising administering to said subject a small molecule connexin 43 hemichannel modulator, wherein said modulator is a compound according to Formula I or Formula II and said ocular disorder is treated:

55. The method of claim 54, wherein said connexin 43 hemichannel modulator is a compound according to Formula I.

56. The method of claim 54, wherein said connexin 43 hemichannel modulator is a compound according to Formula II.

57. The method of claim 54, wherein said connexin 43 hemichannel modulator is tonabersat.

58. The method of claim 57, wherein tonabersat is administered orally.

59. The method of any of claim 54-57 or 58, wherein said ocular disorder characterized in whole or in part by retinal ganglion cell loss is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, and geographic atrophy.