5-HT2A SEROTONIN RECEPTOR INVERSE AGONISTS OR ANTAGONISTS FOR USE IN REDUCING AMYLOID-BETA PEPTIDES AND ACCUMULATION OF AMYLOID PLAQUES

• US 20190117636A1
• Filed: 03/28/2017
• Published: 04/25/2019
• Est. Priority Date: 03/29/2016
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Burstein, Ethan
• Application Number:
  US16/089,316
• Publication Number:
  US 20190117636A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• 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

Described are compounds and compositions for use in methods for reducing the rate of accumulation of amyloid plaques in a subject by administering a 5-HT2A serotonin receptor inverse agonist or antagonist, or pharmaceutically acceptable salts thereof.

Claims

1. A method for reducing the rate of accumulation of amyloid plaques comprising administering an effective amount of a 5-HT2A serotonin receptor inverse agonist or antagonist, or a pharmaceutically acceptable salt thereof to a subject.

4. The method according to claim 1, wherein the subject is a subject in need of reducing the rate of accumulation of amyloid plaques, reducing the concentration of Aβ

peptides (Aβ

), or controlling the production and/or elimination of Aβ

peptides (Aβ

).

5. The method according to claim 1, wherein the subject shows signs of accumulation of amyloid plaques, or the subject has increased concentration or production of Aβ

peptides (Aβ

), prior to being administered the 5-HT2A serotonin receptor inverse agonist or antagonist.

6. The method according to claim 1, wherein prior to being administered the 5-HT2A serotonin receptor inverse agonist or antagonist the subject is identified by one or more of the following:

amyloid plaque imaging using Positron Imaging Tomography (PET);

genetic testing for a mutation in the amyloid precursor protein (APP) gene;

genetic testing for a gene involved in processing amyloid precursor protein (APP);

genetic testing an apolipoprotein E (APOE) ε

4 carrier;

genetic testing for a strong family history of Alzheimer'"'"'s disease;

genetic testing for trisomy for the amyloid precursor protein (APP) gene;

changes in amyloid biomarkers;

changes in tau biomarkers;

reduction from baseline in total whole brain, cortical or hippocampal volume;

increase in brain ventricular volume;

the subject has mild cognitive impairment; and

/or

the subject has increased risk of developing Alzheimer'"'"'s disease or dementia.

7. The method according to claim 6, wherein the increased risk of developing Alzheimer'"'"'s disease or dementia is associated with diabetes, high blood pressure, obesity, smoking, depression, cognitive inactivity;

low education, low physical inactivity, excessive alcohol intake, or subjects who experience severe or repeated head injuries.

8. The method according to claim 1, further comprising identifying a subject to be administered with the 5-HT2A inverse agonist or antagonist, wherein the subject is identified by one or more of the following:

detecting amyloid plaque imaging in the subject using Positron Imaging Tomography (PET);

determining by genetic testing that the subject has a mutation in the amyloid precursor protein (APP) gene;

detecting a mutation on chromosome 21, mutations on chromosome 14 or mutations on chromosome 1 involved in processing amyloid precursor protein (APP);

determining by genetic testing that the subject is an apolipoprotein E (APOE) ε

4 carrier;

determining by genetic testing that the subject has a strong family history of Alzheimer'"'"'s disease;

determining by genetic testing that the subject is trisomic for the amyloid precursor protein (APP) gene;

detecting changes in amyloid biomarkers in the subject;

detecting changes in tau biomarkers in the subject;

detecting reduction from baseline in total whole brain, cortical or hippocampal volume;

detecting increase in brain ventricular volume; and

/or

determining the subject has mild cognitive impairment.

9. The method according to claim 6, wherein the biomarkers are selected from the group consisting of total tau (t-tau) and phosphor-tau (p-tau), Aβ

(1-40), Aβ

(1-42), and Aβ

(1-x) biomarkers.

10. The method according to claim 6, wherein the changes in amyloid biomarkers and tau biomarkers are in cerebrospinal fluid (CSF) or interstitial fluid (ISF) or plasma.

11. The method according to claim 1, wherein the concentration of Aβ

is reduced in the interstitial fluid (ISF) or cerebrospinal fluid (CSF) or plasma.

12. The method according to claim 1, wherein the production of Aβ

is reduced.

13. The method according to claim 1, wherein the elimination of Aβ

is increased.

14. The method according to claim 1, wherein the subject is identified by amyloid plaque imaging using Positron Imaging Tomography (PET) of the brain of the subject.

15. The method according to claim 1, wherein the subject is identified by mutations on chromosome 21, mutations on chromosome 14 or mutations on chromosome 1.

17. The method of claim 1, wherein the Aβ

peptides are selected from the group consisting of Aβ

38, Aβ

40, Aβ

42 and Aβ

43.

18. The method according to claim 17, wherein the Aβ

peptides are Aβ

40 or Aβ

42.

19. The method according to claim 1, wherein the 5-HT2A serotonin receptor inverse agonist or antagonist is a selective 5-1-1T2A serotonin receptor inverse agonist.

20. The method according to claim 1, wherein the 5-HT2A serotonin receptor inverse agonist is selected from the group consisting of volinanserin (MDL 100,907), eplivanserin (SR-46349B), ritanserin, ketanserin, cianserin, fananserin, pruvanserin, pimavanserin (ACP-103, Nuplazid™

), glemanserin, nelotanserin (APD125), AVE8488, ITI-007 and Temanogrel.

21. The method according to claim 1, wherein the 5-1-IT2A serotonin receptor inverse agonist is a selective 5-HT2A serotonin receptor inverse agonist and selected from the group consisting of volinanserin (MDL 100,907), eplivanserin (SR-46349B), pruvanserin, pimavanserin (ACP-103, Nuplazid™

), glemanserin, nelotanserin (APD125), ITI-007 and Temanogrel.

22. The method according to claim 1, wherein the selective 5-HT2A serotonin receptor inverse agonist is pimavanserin (ACP-103, Nuplazid™

) or Volinanserin (MDL 100,907).

23. The method according to claim 1, wherein the selective 5-HT2A serotonin receptor inverse agonist is pimavanserin (ACP-103, Nuptazid™

).

24. The method according to claim 1, additionally comprising administering an effective amount of an agent selected from the group containing an antidepressant, a 5-HT4 serotonin receptor agonist, an M1 muscarinic acetylcholine receptor agonist, an anti-amyloid beta monoclonal antibody, and a beta-secretase 1 (BACE1) inhibitor to the subject.

25. The method according to claim 24, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

2. A method for reducing the concentration of Aβ

peptides (Aβ

) in a subject comprising administering an effective amount of a 5-HT2A serotonin receptor inverse agonist or antagonist, or a pharmaceutically acceptable salt thereof to the subject, wherein the concentration is in the brain of the subject.

3. A method for controlling the production and/or elimination of Aβ

peptides (Aβ

) comprising administering an effective amount of a 5-HT2A serotonin receptor inverse agonist or antagonist, or a pharmaceutically acceptable salt thereof to a subject, wherein the production is in the brain of the subject.

16. (canceled)

26-39. -39. (canceled)