METHODS AND COMPOUNDS FOR TREATMENT OF NEURODEGENERATIVE DISORDERS

• US 20120010178A1
• Filed: 10/21/2009
• Published: 01/12/2012
• Est. Priority Date: 10/21/2008
• Status: Abandoned Application

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Rubin, Lee, Sinor, Amy, Makhortova, Nina Ruslanovna, Yang, Yin Miranda, Bennett, Monica Hayhurst
• Application Number:
  US13/125,376
• Publication Number:
  US 20120010178A1
• Time in Patent Office: Days
• US Class Current: 514/158
• 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 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• 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

Abstract

Methods, compounds and compositions for promoting motor neuron survival and the treatment of a neurodegenerative disorders such as Spinal Muscular Atrophy (SMA) are described herein.

Claims

1. A method of promoting motor neuron cell survival, the method comprising:

contacting a motor neuron cell with a compound of formula (VI)

7. The method of claim 1, wherein the motor neuron comprises a mutation in gene encoding SMN1 or a mutation in gene encoding superoxide mutase 1 (SOD1).

9. The method of claim 1, wherein the motor neuron comprises a G->

A mutation at position 93 of gene encoding SOD1.

10. The method of claim 1, wherein the compound modulates survival of motor neuron (SMN) protein levels.

22. The method of claim 1, wherein the contact is in vitro.

23. The method of claim 1, wherein the contact is in vivo.

25. The method of claim 23, wherein in vivo contact is in a subject, where the subject is selected for treatment of a neurodegenerative disorder characterized by degeneration of motor neurons.

27. The method of claim 25, wherein the neurodegenerative disorder is characterized by a mutation in the SMN gene or by diminished levels of SMN protein.

29. The method of claim 25, wherein the neurodegenerative disorder is spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS).

2-6. -6. (canceled)

8. (canceled)

11-21. -21. (canceled)

24. (canceled)

26. (canceled)

28. (canceled)

30. (canceled)

31. A method of promoting motor neuron survival, the method comprising:

contacting a motor neuron with a compound that modulates a biological pathway selected from the group consisting of PI-3K signaling pathway, Akt signaling pathway, MAPK signaling pathway, PDGF pathway, RAS pathway, eIF2 pathway, glycogen synthase kinase (GSK) pathway, PKR pathway, Insulin Receptor Pathway, mTOR pathway, EGF pathway, NGF pathway, FGF pathway, TGF pathway, BMP pathway, receptor tyrosine kinase (RTK) pathway, and any combinations thereof or a target selected from the group consisting of Na⁺/K⁺ channel, MAPK, cannobinoid receptor, GPCR, Ca²⁺ channel, K⁺ channel, PDE5, GSK/CDK, PKR, CDK2, CDK5, GSK-313, IKK-2, IKK-213, proteasome, BMP/TGFbeta receptor, dopamine receptor, and any combinations thereof.

37. The method of claim 31, wherein the compound is selected from the group consisting of formula (I):

38. The method of claim 31, wherein the motor neuron comprises a mutation in gene encoding SMN1 or a mutation in gene encoding superoxidase mutase (SOD1).

41. The method of claim 31, wherein the compound modulates survival of motor neuron (SMN) protein levels.

52. The method of claim 31, wherein the contact is in vivo.

54. The method of claim 52, wherein in vivo contact is in a subject, where the subject is selected for treatment of a neurodegenerative disorder characterized by degeneration of motor neurons.

56. The method of claim 54, wherein the neurodegenerative disorder is characterized by a mutation in the SMN gene or by diminished levels of SMN protein.

58. The method of claim 54, wherein the neurodegenerative disorder is spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS).

59. The method of claim 31, wherein the compound is selected from the group consisting of Kenpaullone, Alsterpaullone, 2-cyanoethyl-alsterpaullone, CHIR9814, CHIR99021, GSK1, GSK2, GSK6, GSK7, GSK8, GSK13, and any combinations thereof.

32-36. -36. (canceled)

39. (canceled)

40. The method of 38, wherein the motor neuron comprises a G->

A mutation at position 93 of gene encoding SOD1.

42-51. -51. (canceled)

53. (canceled)

55. (canceled)

57. (canceled)

60-119. -119. (canceled)

120. A method of increasing SMN protein levels in a cell, the method comprising:

contacting a cell with a compound, wherein the compound modulates a biological pathway selected from the group consisting of PI-3K signaling pathway, Akt signaling pathway, MAPK signaling pathway, PDGF pathway, RAS pathway, eIF2 pathway, GSK signaling pathway, PKR pathway, Insulin Receptor Pathway, mTOR pathway, EGF pathway, NGF pathway, FGF pathway, TGF pathway, BMP pathway, receptor tyrosine kinase (RTK) pathway, and any combinations thereof or a target selected from the group consisting Na⁺/K⁺ channel, MAPK, cannobinoid receptor, GPCR, Ca²⁺ channel, K⁺ channel, PDE5, GSK/CDK, PKR, CDK2, IKK-2, proteasome, BMP/TGFbeta receptor, dopamine receptor, and any combinations thereof.

121-133. -133. (canceled)