COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISEASE

• US 20140378460A1
• Filed: 08/27/2012
• Published: 12/25/2014
• Est. Priority Date: 08/25/2011
• Status: Abandoned Application

• Current Assignee: Cognition Therapeutics, Inc.
• Original Assignee: Cognition Therapeutics, Inc.
• Inventors: Catalano, Susan M., Rishton, Gilbert, Izzo, Nicholas J.
• Application Number:
  US14/241,026
• Publication Number:
  US 20140378460A1
• Time in Patent Office: Days
• US Class Current: 514/239.5
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• 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 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 211/15 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 233/91 with carbon atoms of the carboxamide groups bound to acyclic carbon atoms
• CPC Class Codes: C07C 267/00 Carbodiimides
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 235/04 Benzimidazoles; Hydrogenated benzimidazoles
• CPC Class Codes: C07D 317/46 condensed with one six-membered ring
• CPC Class Codes: G01N 2333/705 Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2500/10 involving cells
• CPC Class Codes: G01N 33/5058 Neurological cells

Abstract

This invention relates to the use sigma-2 receptor antagonists, and of pharmaceutical compositions comprising such compounds, in methods for inhibiting Abeta-associated synapse loss or synaptic dysfunction in neuronal cells, modulating an Abeta-associated membrane trafficking change in neuronal cells, and treating cognitive decline associated with Abeta pathology and more broadly treating with such compounds and compositions neurodegenerative diseases and disorders associated with Abeta pathology. This invention also relates to methods for screening compounds for activity in inhibiting cognitive decline on the basis of their ability to bind to a sigma-2 receptor.

Claims

1. A method/use for inhibiting an amyloid beta effect on a neuronal cell comprising administering an effective amount of a composition comprising

a selective sigma-2 receptor antagonist compound in an amount effective to inhibit amyloid beta oligomer binding in said cell;

and

a pharmaceutically acceptable carrier.

2. The method/use of claim 1 wherein the compound is not

3. The method/use of claim 1, wherein the compound is administered in an amount also effective to inhibit membrane trafficking deficits in said cell, said membrane trafficking effects being associated with exposure of said cell to soluble amyloid beta oligomers.

4. The method/use of claim 1, wherein the compound is in an amount effective to inhibit both the oligomer binding and synapse loss associated with exposure of the cell to soluble amyloid beta oligomer in said cell.

5. The method/use of claim 1, wherein the compound is administered in an amount effective to inhibit a soluble amyloid beta oligomer-mediated cognitive effect.

10. The method/use of claim 1 wherein the compound is of Formula VIIIq:

11. The method/use of claim 1 wherein said compound is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:

12. The method/use of claim 11 wherein the compound is selected from

13. The method/use of claim 2 wherein the compound is of Formula VIIIo

14. The method/use of claim 13 wherein said compound is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:

15. The method/use of claim 1 wherein said compound is selected from an antibody, or active binding fragment thereof, wherein the antibody or fragment is specific for a sigma-2 receptor.

17. The method/use of claim 1 for inhibiting amyloid beta oligomer-induced synaptic dysfunction of a neuronal cell;

comprising contacting the cell with the composition comprising a sigma-2 receptor antagonist compound in an amount effective to inhibit amyloid beta oligomer binding in said cell, said dysfunction being associated with exposure of the cells to soluble amyloid beta oligomer.

18. The method/use of claim 1 for inhibiting suppression of long term potentiation in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the composition comprising a sigma-2 receptor antagonist compound.

19. The method/use of claim 1 for inhibiting cognitive decline in a subject exhibiting, or at risk of exhibiting, cognitive decline, comprising administering a therapeutically effective amount of the composition comprising a sigma-2 receptor antagonist compound to the subject.

20. The method/use of claim 1 for inhibiting cognitive decline in a subject associated with an amyloid beta oligomer effect on central neurons comprising administering a therapeutically effective amount of the composition comprising a sigma-2 receptor antagonist compound to a subject afflicted with said cognitive decline.

21. The method/use of claim 1 for the treatment of mild cognitive impairment in Alzheimer'"'"'s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition comprising a sigma-2 receptor antagonist compound.

22. The method/use of claim 1 wherein the sigma-2 antagonist compound has one or more of the following additional properties:

(a) it selectively binds to a sigma-2 receptor with at least 10-fold, 20-fold, 50-fold, or 100-fold greater affinity compared to one or more non-sigma CNS receptors, wherein the compound binds to a sigma-2 receptor with a K_i less than 200 nM, 150 nM, 100 nM or 60 nM

(b) it inhibits Abeta oligomer binding to or synapse loss in neuronal cells said loss being associated with exposure of the cells to Abeta oligomer;

(c) it inhibits membrane trafficking abnormalities in a central neuron, the abnormalities being associated with exposure of said cell to one or more Abeta oligomers;

(d) it fails to affect trafficking or synapse number in central neurons in the absence of amyloid beta oligomers.

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

16. (canceled)

23. The method/use for identifying a selective, high affinity sigma-2 antagonist compound comprising:

selecting a compound for testing on the basis of its ability to selectively bind to a sigma-2 receptor with at least 10-fold, 20-fold, 50-fold, or 100-fold greater affinity compared to one or more non-sigma CNS receptors, wherein the compound binds to a sigma-2 receptor with a K_i less than 200 nM, 150 nM, 100 nM or 60 nM;

contacting a neuronal cell with the compound; and

determining whether said compound has one or more of the following additional properties;

(a) it inhibits amyloid beta oligomer binding or synapse loss in a central neuron, said loss being associated with exposure of the neuron to amyloid beta oligomer;

(b) it inhibits membrane trafficking abnormalities in a central neuron, the abnormalities being associated with exposure of said cell to one or more amyloid beta oligomers; and

(c) it fails to affect trafficking or synapse number in the absence of amyloid beta oligomers.

24. A composition for inhibiting an amyloid beta effect on a neuronal cell comprising

a selective, sigma-2 receptor antagonist compound in an amount effective to inhibit amyloid beta oligomer binding in said cell;

and

a pharmaceutically acceptable carrier.

25. The composition of claim 24 comprising a sigma-2 receptor antagonist wherein the compound is not

26. The composition of claim 24 wherein the compound is of Formula VIIIq:

27. The composition of claim 24 wherein said compound is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:

28. The composition of claim 27 wherein the compound is selected from

29. The composition of claim 24 wherein the compound is of Formula VIIIo

30. The composition of claim 29 wherein said compound is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof:

31. The composition of claim 24 wherein said compound is selected from an antibody, or active binding fragment thereof, wherein the antibody or fragment is specific for a sigma-2 receptor.

32. (canceled)