# US 2013/0156705 A1 · Bivalent multifunctional ligands targeting a[beta] oligomers as treatment for alzheimer's disease

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- Number: US 2013/0156705 A1
- Document ID: US20130156705A1
- Status: Published application
- Kind: A1
- Application number: 13/810,826
- Filed: 2011-07-14
- Published: 2013-06-20
- Earliest claimed: 2010-07-19
- Assignees: Virginia Commonwealth University
- Inventors: Shujin Zhang; Tai Liang Guo
- Web page: https://patentgrep.com/patent/US20130156705A1

## CPC

- C07J 43/003: {not condensed}
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/575: substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
- A61K 49/0052: {Small organic molecules (oligomers, polymers, dendrimers A61K49/0054)}
- A61P 25/00: Drugs for disorders of the nervous system
- 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
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- C07J: STEROIDS (seco-steroids C07C)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Bivalent multifunctional Aβ oligomerization inhibitors (BMAOIs) that target multiple risk factors involved in Alzheimer's disease are provided. The BMAOIs are useful for the treatment and/or prevention of Alzheimer's disease, as well as for diagnostic imaging of Aβ plaques in brain tissue. The BMAOIs comprise i) an Aβ oligomer (ApO)-inhibitor moiety which may have antioxidant activity (e.g. curcumin, curcumin derivatives, curcumin hybrids, resveratrol, etc.); ii) a cell membrane/lipid raft (CM/LR) anchoring moiety (e.g. cholesterol, cholesterylamine, a steroid, etc.); and iii) a spacer or linker moiety that stably links i)

## Claims

### Claim 1

A bivalent multifunctional AP oligomerization inhibitor (BMAOI) comprising
i) a multifunctional AP oligomer (AβO)-inhibitor moiety;
ii) a cell membrane/lipid raft (CM/LR) anchor; and
iii) a spacer moiety which forms a chemical linkage between said AβO-inhibitor moiety and said CM/LR anchor.

### Claim 2 (depends on 1)

The BMAOI of claim 1, wherein said AβO-inhibitor moiety is selected from the group consisting of curcumin, resveratrol, and a hybrid molecule that comprises curcumin.

### Claim 3 (depends on 2)

The BMOI of claim 2, wherein said hybrid molecule comprises curcumin and melatonin.

### Claim 4 (depends on 1)

The BMAOI of claim 1, wherein said CM/LR anchor is selected from the group consisting of cholesterol, a cholesterol derivative, and a steroid.

### Claim 5 (depends on 4)

The BMAOI of claim 4, wherein said cholesterol derivative is cholesterylamine.

### Claim 6 (depends on 4)

The BMAOI of claim 4, wherein said steroid is diosgenin.

### Claim 7 (depends on 1)

The BMAOI of claim 1, wherein said spacer moiety is 21 atoms in length.

### Claim 8 (depends on 2)

The BMAOI of claim 2, wherein said AβO-inhibitor moiety is curcumin and said spacer moiety is chemically linked to carbon at position C4 of said curcumin.

### Claim 9 (depends on 4)

The BMAOI of claim 4, wherein said CM/LR anchor is cholesterol and said spacer moiety is chemically linked to O attached to position C3 of said cholesterol.

### Claim 10 (depends on 5)

The BMAOI of claim 5, wherein said spacer moiety is chemically linked to N attached to position C3 of said cholesterylamine.

### Claim 11 (depends on 1)

The BMAOI of claim 1, wherein said AβO-inhibitor moiety has antioxidant activity.

### Claim 12 (depends on 1)

The BMAOI of claim 1, wherein said AβO-inhibitor moiety has metal chelating properties.

### Claim 13

A method of preventing or treating Alzheimer's disease (AD) in a patient in need thereof, comprising the step of
administering to said patient a bivalent multifunctional Aβ oligomerization inhibitor (BMAOI) comprising
i) an AP oligomer (AβO)-inhibitor moiety;
ii) a cell membrane/lipid raft (CM/LR) anchor; and
iii) a spacer moiety which forms a chemical linkage between said AβO-inhibitor moiety and said CM/LR anchor, wherein said BMAOI is administered in an amount sufficient to prevent or treat said AD in said patient.

### Claim 14 (depends on 13)

The method of claim 13, wherein said bivalent multifunctional ligand is compound 14,

### Claim 15 (depends on 13)

The method of claim 13, wherein said bivalent multifunctional ligand is compound 51,

### Claim 16

A method of imaging or visualizing β-amyloid (Aβ) plaques in brain tissue, comprising the steps of
exposing said brain tissue to at least one bivalent multifunctional Aβ oligomerization inhibitor (BMAOI) comprising
i) an Ap oligomer (AβO)-inhibitor moiety;
ii) a cell membrane/lipid raft (CM/LR) anchor; and
iii) a spacer moiety which forms a chemical linkage between said AβO-inhibitor moiety and said CM/LR anchor, wherein said step of exposing is carried out under conditions that allow said at least one BMAOI to associate with said Aβ plaques in said brain tissue;
exposing said brain tissue to a source of electromagnetic radiation; and
detecting fluorescence emitted from BMAOIs associated with said Aβ plaques.

### Claim 17 (depends on 16)

The method of claim 16, wherein said bivalent multifunctional ligand is compound 14,

### Claim 18 (depends on 16)

The method of claim 16, wherein said bivalent multifunctional ligand is compound 51,