Small molecules that mimic or antagonize actions of granulocyte colony-stimulating-factor (G-CSF)

Patent metadata

Field	Value
Publication number	US-10376495-B2
Application number	US-201715821634-A
Country	US
Kind code	B2
Filing date	Nov 22, 2017
Priority date	Nov 23, 2016
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

Abstract

Described herein are compound for the modulation of the G-CSF receptor. The compounds may act as agonists, antagonists, and/or mixed or partial agonists/antagonists of G-CSF. Further provided herein are methods of treating a condition, including, for example, a neurodegenerative disease, by administering a compound as detailed herein.

First claim

We claim:

1. A method of treating a condition in a subject, the method comprising administering a compound to the subject,
wherein the compound is

wherein the condition is selected from the group consisting of neurodegenerative disease, stroke, traumatic brain injury (TBI), impaired motor function, and impaired cognitive function.

2. The method of claim 1 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), prion disease, motor neuron disease, Huntington's Disease, spinocerebellar ataxia, and spinal muscular atrophy.

3. The method of claim 1 , wherein the compound decreases amyloid burden, enhances neurogenesis, enhances synaptogenesis, or enhances cognitive performance, or a combination thereof.

4. The method of claim 1 , wherein the compound binds the Granulocyte Colony-Stimulating Factor (G-CSF) Receptor.

5. The method of claim 1 , wherein the compound displaces at least 50% of G-CSF from the G-CSF receptor.

6. The method of claim 1 , wherein the compound is a peripheral antagonist of the G-CSF receptor.

7. The method of claim 1 , wherein the compound is a central agonist of G-CSF receptor.

8. The method of claim 1 , wherein expression of Bcl2 is increased.

9. The method of claim 1 , wherein expression of PKCδVIII is increased.

10. The method of claim 1 , wherein expression of Bax is decreased.

11. The method of claim 1 , wherein leukopoiesis is minimally affected or is not affected.

12. The method of claim 1 , wherein the compound is co-administered with a G-CSF polypeptide.

Assignees

• Univ South Florida
• Us Gov Veterans Affairs
• H Lee Moffitt Cancer Center And Res Instritute Inc
• The Us Gov As Represented By The Department Of Veterans
• H Lee Moffitt Cancer Ct & Res

Inventors

• Sanchez-Ramos Juan
• Sava Vasyl
• Song Shijie
• Sebti Said

Classifications

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• C07D233/60

  with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms · CPC title

• A61K38/193

  Colony stimulating factors [CSF] · CPC title

• A61P25/28

  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 title

• A61K31/4174 Primary

  Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole · CPC title