Small molecule stimulators of neuronal growth

• US 20060025379A1
• Filed: 05/26/2005
• Published: 02/02/2006
• Est. Priority Date: 05/26/2004
• Status: Active Grant

• Current Assignee: California Institute of Technology
• Original Assignee: California Institute of Technology
• Inventors: Hsieh-Wilson, Linda C., Mabon, Ross, Tully, Sarah E., Gama, Cristal I.
• Granted Patent: US 7,638,503 B2
• Time in Patent Office: Days
• US Class Current: 514/54
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 3/04 Disaccharides
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan

Abstract

Provided herein are small molecule stimulators of neuronal growth, their preparation, and their use for treatment of neurological disorders. In one embodiment, provided herein are methods of treatment, prevention, or amelioration of a variety of medical conditions associated with neurological disorders using the compounds and compositions provided herein.

Claims

1. A compound of formula:

2. The compound of claim 1, wherein n is 0-50.

3. The compound of claim 1, wherein n is 0-10.

4. The compound of claim 1, wherein n is 0, 1, 2, 3 or 4.

5. The compound of claim 1, wherein R⁵ is lower alkenyl.

6. The compound of claim 1, wherein R⁵ is allyl.

7. The compound of claim 1, R¹ is selected from hydrogen, sulfate, phosphate and carboxylate.

8. The compound of claim 1, wherein R¹ is sulfate.

9. The compound of claim 1, wherein R¹ is hydrogen.

10. The compound of claim 1, wherein R² is selected from hydrogen, sulfate, phosphate and carboxylate.

11. The compound of claim 1, wherein R² is sulfate.

12. The compound of claim 1, wherein R³ is selected from hydrogen, sulfate, phosphate and carboxylate.

13. The compound of claim 1, wherein R³ is sulfate.

14. The compound of claim 1, wherein R³ is hydrogen.

15. The compound of claim 1, wherein R⁴ is selected from hydrogen, sulfate, phosphate and carboxylate.

16. The compound of claim 1, wherein R⁴ is sulfate.

17. The compound of claim 1, wherein R⁴ is hydrogen.

18. The compound of claim 1, wherein the compound has formula:

19. The compound of claim 1, wherein the compound has formula:

20. The compound of claim 1, wherein the compound has formula:

21. The compound of claim 1, wherein the compound has formula:

22. The compound of claim 1, wherein the compound has formula:

23. The compound of claim 1, wherein the compound has formula:

24. The compound of claim 1, wherein the compound has formula:

25. The compound of claim 1, wherein the compound has formula:

26. The compound of claim 1, wherein the compound has formula:

27. The compound of claim 1, wherein the compound has formula:

28. The compound of claim 1, wherein the compound has formula:

29. A substantially pure compound of claim 1.

42. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

43. A method of modulating neuronal growth, wherein the method comprises administering an effective amount of a compound of claim 1.

44. The method of claim 43, wherein the compound promotes regeneration of an injured or severed nerve or nerve tissue or promotes outgrowth in a neuronal cell.

45. The method of claim 43, wherein the neuronal cell is a neuronal cell from brain, CNS or peripheral nerves.

46. The method of claim 44, wherein the compound promotes neuronal growth in a cultured neuron.

47. The method of claim 46, wherein the cultured neuron is hippocampal neurons, dopaminergic neurons or dorsal root ganglion neuron.

48. A method of inducing growth of differentiated neural stem cells, wherein the method comprises administering an effective amount of a compound of claim 1.

49. A method of treating symptoms associated with a neurological disorder, wherein the method comprises administering an effective amount of a compound of claim 1 to a subject in thereof.

50. The method of claim 49, wherein the disorder is CNS lesions, gliosis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease or neuronal degeneration.

51. The method of claim 50, wherein the disorder is a spinal cord trauma.

52. A method of modulating the activity of fibroblast growth factors, wherein the method comprises administering an effective amount of a compound of claim 1.

53. The method of claim 43, wherein the compound of claim 1 is administered in combination with a nerve growth factor.

54. The method of claim 52, wherein the compound of claim 1 is administered in combination with a fibroblast growth factor.

55. A method for screening for small molecule inducers of neuronal growth, wherein the method comprises:

applying to a cultured neuron a small molecule of claim 1, and determining an increase in percent growth in axon length of treated versus untreated neuron.

56. The method of claim 55, wherein the increase in mean axon length relative to an untreated cell between about 10% to about 50%.

57. An article of manufacture comprising packaging material;

a compound of claim 1 within the packaging material; and

a label that indicates that the compound, or pharmaceutically acceptable derivative thereof, is used for a treatment, prevention or amelioration of one or more symptoms associated with neurological disorders.

30. A polysaccharide compound containing a repeating dimer unit of formula I:

31. The polysaccharide compound of claim 30, wherein R¹ and R² are sulfate.

32. The polysaccharide compound of claim 30, wherein R¹ and R² are sulfate.

33. The polysaccharide compound of claim 30, wherein the dimer unit has formula:

34. A compound of formula R-L-R, wherein R is

35. The compound of claim 34, wherein the linker has formula:

36. The compound of claim 35, wherein n1 is 1-50.

37. The compound of claim 35, wherein n1 is 1-10.

38. The compound of claim 35, wherein n1 is 1, 2 or 3.

39. The compound of claim 38, wherein the compound has formula:

40. A glycopolymer comprising:

a polymer backbone P conjugated with a compound R via a linker L, wherein R has formula;

41. The glycopolymer of claim 40 selected from: