Inhibitors of the fkbp51 protein from a high-throughput drug screen and methods of use

Patent metadata

Field	Value
Publication number	US-2018296554-A1
Application number	US-201815949703-A
Country	US
Kind code	A1
Filing date	Apr 10, 2018
Priority date	Jun 30, 2015
Publication date	Oct 18, 2018
Grant date	—

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 person or animal having a neurodegenerative disease or condition, or depression, a stress disorder, and/or an 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.

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 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.

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

6 . 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.

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

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

9 . The method according to claim 1 , wherein the method further comprises treating the person or animal with one or more drugs or compounds approved for treating a neurodegenerative disease, or for treating depression, a stress disorder, or an anxiety disorder.

10 . The method according to claim 9 , wherein said approved drug or compound is one or more of donepezil, galantamine, vivastigmine, memantine, rivastigmine, or selegiline; or one or more of monoamine oxidase (MAO) inhibitors such as phenelzine, tranylcypromine, isocarboxazid, or selegiline; antiepileptic drugs; selective serotonin reuptake inhibitors (SSRI), such as citalopram, escitalopram, fluvoxamine, fluoxetine, vortioxetine, paroxetine, sertraline, rasagiline, selegiline, L-dopa, carbidopa, or benserazide, or an isomer or analog thereof; serotonin-norepinephrine reuptake inhibitors (SNRI), such as venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, sibutramine, or milnacipran; tricyclic antidepressants (TCAs), such as amitriptyline, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine; 3,4-methylenedioxy-N-methylamphetamine (MDMA); propranolol; or ziprasidone, or risperidone, prazosin, mirtazapine, venlafaxine, lithium, bupropion, trazodone, or carbamazepine, or an isomer or analog thereof.

11 . 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.

12 . 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.

13 . A method for inhibiting activity or function of the FKBP51 protein in a cell, the method comprising contacting said cell with an effective amount of a compound or drug, or a composition comprising said compound or drug, that inhibits activity or function of a FKBP51 protein; or
a method for screening for a compound or drug that inhibits FKBP51 protein, said method comprising contacting a cell with a compound or drug to be screened, and determining whether the compound or drug inhibits the activity or function of a FKBP51 protein in the cell.

14 . The method according to claim 13 , wherein said cell is contacted in an in vitro environment.

15 . The method according to claim 13 , wherein said cell is contacted in an in vivo environment.

16 . The method according to claim 13 , wherein said cell is a human cell.

17 . The method according to claim 13 , wherein the compound or drug is one that lessens or attenuates the suppressive effect of FKBP51 on glucocorticoid receptor (GR) activity.

18 . The method according to claim 13 , wherein the compound or drug is benztropine, clonidine, pimozide, thioridazine, trifluoperazine, or triflupromazine, or a pharmaceutically or physiologically acceptable salt thereof.

19 . A composition comprising one or more of benztropine, clonidine, pimozide, thioridazine, trifluoperazine, or triflupromazine, and optionally a pharmaceutically or physiologically acceptable carrier, buffer, or diluent; or a kit comprising in one or more containers, one or more of benztropine, clonidine, pimozide, thioridazine, trifluoperazine, or triflupromazine, and optionally a pharmaceutically or physiologically acceptable carrier, buffer, or diluent.

20 . The composition or kit according to claim 19 , wherein said composition or kit further comprises one or more of donepezil, galantamine, vivastigmine, memantine, rivastigmine, or selegiline; or one or more of monoamine oxidase (MAO) inhibitors such as phenelzine, tranylcypromine, isocarboxazid, or selegiline; antiepileptic drugs; selective serotonin reuptake inhibitors (SSRI), such as citalopram, escitalopram, fluvoxamine, fluoxetine, vortioxetine, paroxetine, sertraline, rasagiline, selegiline, L-dopa, carbidopa, or benserazide, or an isomer or analog thereof; serotonin-norepinephrine reuptake inhibitors (SNRI), such as venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, sibutramine, or milnacipran; tricyclic antidepressants (TCAs), such as amitriptyline, desipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine; 3,4-methylenedioxy-N-methylamphetamine (MDMA); propranolol; or ziprasidone, or risperidone, prazosin, mirtazapine, venlafaxine, lithium, bupropion, trazodone, or carbamazepine, or an isomer or analog thereof.

Assignees

• Univ South Florida

Inventors

• Sabbagh Jonathan Jacob
• Dickey Chad

Classifications

• A61K31/138

  Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377) · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/15

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

• A61K31/42

  Oxazoles · CPC title