# US 11,896,644 B2 · Inhibition of beta-arrestin oligomerization in tauopathy

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- Number: US 11,896,644 B2
- Document ID: US11896644B2
- Status: Granted
- Kind: B2
- Application number: 17/798,041
- Filed: 2021-02-08
- Published: 2023-04-13
- Granted: 2024-02-13
- Earliest claimed: 2020-02-07
- Assignees: University of South Florida
- Applicants: University of South Florida
- Inventors: Jung A. Woo; Stephen Bryant Liggett; David E. Kang; Yu Chen; Eric Lewandowski
- Web page: https://patentgrep.com/patent/US11896644B2

## CPC

- A61K 38/1709: {from mammals}
- C07K 14/47: from mammals
- A61K 31/42: Oxazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/501: not condensed and containing further heterocyclic rings
- 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
- A61P 35/00: Antineoplastic agents
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2217/077: heterozygous knock out animals displaying phenotype
- A01K 2227/105: Murine
- A01K 2267/0318: Animal model for neurodegenerative disease, e.g. non- Alzheimer's
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 2310/14: interfering nucleic acids [NA]
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

As disclosed herein, β-arrestin1 and β-arrestin2 levels are highly elevated in brains of FTLD-tau patients suggesting that both β-arrestin1 and β-arrestin2 are elevated in the brains of patients with AD and FLTD. The current work also shows that when β-arrestin2 is overexpressed, tau levels become elevated. The data indicate that β-arrestin2 reduces tau clearance by impairing p62-mediated autophagy, a role carried out by the oligomerized form of β-arrestin2. Therefore, disclosed herein are β-arrestin oligomerization inhibitors that can be used to prevent β-arrestin oligomerization and therefore the accumulation of tau in cells, i.e. tauopathy. Also disclosed are methods of treating a tauopathy in a subject that involve administering to the subject a therapeutically effective amount of a β-arrestin oligomerization inhibitor disclosed herein.

## Claims

### Claim 1

A method of treating a tauopathy in a subject, the method comprising administering to the human subject a therapeutically effective amount of a β-arrestin oligomerization inhibitor, wherein the inhibitor is a compound having a structure or a pharmaceutically-acceptable salt thereof selected from the group consisting of:
wherein R1 is hydrogen or an alkyl group;
wherein Ar is an aryl group; and
wherein when R1 is an alkyl group, the stereochemistry at Ca is racemic, substantially R, or substantially S;
wherein Ar is an aryl group;
wherein R2 and R3 are, independently, hydrogen or an alkyl group; and Ar is an aryl group;
wherein Ar1 and Ar2 are, independently, an aryl group; and
wherein X is CH2 or C═O;
wherein Ar1 and Ar2 are, independently, an aryl group; and

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is hydrogen.

### Claim 3 (depends on 1)

The method of claim 1, wherein when the compound or pharmaceutically-acceptable salt thereof is (a), Ar is an unsubstituted or substituted phenyl group.

### Claim 4 (depends on 1)

The method of claim 1, wherein when the compound or pharmaceutically-acceptable salt thereof is (a), Ar is a phenyl group substituted with one or more halogen atoms.

### Claim 5 (depends on 1)

The method of claim 1, wherein R1 is a C1 to C10 alkyl group.

### Claim 6 (depends on 1)

The method of claim 1, wherein the tauopathy is selected from the group consisting of Alzheimer's disease, Pick's disease, Frontotemporal dementia, Frontotemporal dementia with Parkinsonism linked to chromosome 17, progressive supranuclear palsy, Corticobasal degeneration, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis/parkinsonism-dementia complex, argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal lobar degeneration, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, Tangle only dementia, multi-infarct dementia, ischemic stroke, chronic traumatic encephalopathy, traumatic brain injury, and stroke.

### Claim 7 (depends on 1)

The method of claim 1, wherein the tauopathy is frontotemporal lobar degeneration.