Inhibitors of the FKBP51 protein from a high-throughput drug screen and methods of use

Patent metadata

Field	Value
Publication number	US-9962379-B2
Application number	US-201615209594-A
Country	US
Kind code	B2
Filing date	Jul 13, 2016
Priority date	Jun 30, 2015
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

The subject invention concerns materials and methods for treating depression, stress disorders, such as PTSD, anxiety disorders, and/or a neurodegenerative disease or condition in a person or animal. In one embodiment, a person or animal in need of treatment is administered one or more compounds or drugs, or a composition comprising the one or more compounds or drugs, that inhibit FKBP51 activity or function. The subject invention also concerns a method for inhibiting activity of the FKBP51 protein in a cell. The subject invention also concerns methods of screening for compounds or drugs that inhibit the FKBP51 protein.

First claim

We claim:

1. A method for treating a neurodegenerative disease or condition, or depression, a stress disorder, and/or an anxiety disorder in a person or animal having said neurodegenerative disease or condition, depression, stress disorder, and/or anxiety disorder, the method comprising administering to the person or animal a therapeutically effective amount of one or more compounds or drugs, or a composition comprising said one or more compounds or drugs, that inhibits FKBP51 activity or function; and administering to the person or animal one or more drugs or compounds approved for treating a neurodegenerative disease or condition, or for treating depression, a stress disorder, or an anxiety disorder, or a composition comprising said one or more approved drugs or compounds, wherein said approved drug or compound is 3,4-methylenedioxy-N-methylamphetamine (MDMA), propranolol, or ziprasidone.

2. The method according to claim 1 , wherein the person or animal exhibits increased levels of FKBP51 protein relative to a control.

3. The method according to claim 1 , wherein the compound or drug is one that lessens or attenuates the suppressive effect of FKBP51 on glucocorticoid receptor (GR) activity.

4. The method according to claim 1 , wherein the compound or drug is benztropine, clonidine, pimozide, thioridazine, trifluoperazine, or triflupromazine, or a pharmaceutically or physiologically acceptable salt thereof.

5. The method according to claim 1 , wherein the person or animal exhibits one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene, and wherein said one or more SNPs are associated with elevated levels of FKBP51 protein.

6. The method according to claim 1 , wherein said compound or drug is provided in the form of a pharmaceutically or physiologically acceptable salt.

7. The method according to claim 1 , wherein the method further comprises a step of determining whether the person or animal exhibits elevated levels of FKBP51 protein.

8. The method according to claim 1 , wherein the stress disorder is a post-traumatic stress disorder (PTSD).

9. The method according to claim 1 , wherein the neurodegenerative disease is Alzheimer's disease.

10. The method according to claim 1 , wherein the method further comprises a step of determining whether the person or animal exhibits one or more SNPs that are associated with elevated levels of FKBP51 protein.

11. The method according to claim 1 , wherein said approved drug or compound is 3,4-methylenedioxy-N-methylamphetamine (MDMA).

12. The method according to claim 1 , wherein said approved drug or compound is propranolol.

13. The method according to claim 1 , wherein said approved drug or compound is ziprasidone.

14. The method according to claim 1 , wherein said method further comprises treating the person or animal with one or more of donepezil, galantamine, vivastigmine, memantine, rivastigmine, or selegiline; monoamine oxidase (MAO) inhibitors; antiepileptic drugs; selective serotonin reuptake inhibitors (SSRI); serotonin-norepinephrine reuptake inhibitors (SNRI); tricyclic antidepressants (TCAs); risperidone, prazosin, mirtazapine, venlafaxine, lithium, bupropion, trazodone, or carbamazepine.

15. The method according to claim 14 , wherein said MAO inhibitor is phenelzine, tranylcypromine, isocarboxazid, or selegiline.

16. The method according to claim 14 , wherein said SSRI is citalopram, escitalopram, fluvoxamine, fluoxetine, vortioxetine, paroxetine, sertraline, rasagiline, selegiline, L-dopa, carbidopa, or benserazide.

17. The method according to claim 14 , wherein said SNRI is venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, sibutramine, or milnacipran.

18. The method according to claim 14 , wherein said TCA is amitriptyline, desipramine, doxepin, imipramine, nortriptyline, or protriptyline.

Assignees

• Sabbagh Jonathan Jacob
• Dickey Chad
• Univ South Florida
• Us Gov Veterans Affairs

Inventors

• Sabbagh Jonathan Jacob
• Dickey Chad

Classifications

• A61K31/46

  8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine · CPC title

• A61K31/135

  having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} · CPC title

• A61K31/4168

  having a nitrogen attached in position 2, e.g. clonidine · CPC title

• A61K31/137

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61K31/15

  Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) {; Imines (C—N=C)} · CPC title