# US 10,479,800 B2 · Compositions and methods for regulating glucose homeostasis and insulin action

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- Number: US 10,479,800 B2
- Document ID: US10479800B2
- Status: Granted
- Kind: B2
- Application number: 15/341,961
- Filed: 2016-11-02
- Published: 2017-08-24
- Granted: 2019-11-19
- Earliest claimed: 2012-06-20
- Assignees: University of Virginia Patent Foundation
- Applicants: University of Virginia Patent Foundation
- Inventors: Kyle Hoehn; Brandon Kenwood
- Web page: https://patentgrep.com/patent/US10479800B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- G01N 33/5014: {for testing toxicity}
- G01N 33/5079: {Mitochondria}
- G01N 2500/10: involving cells
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

The present invention encompasses the use of compounds for a novel approach to treat and prevent diseases, conditions, and disorders such as diabetes and ischemic reperfusion injury. Compounds of the invention, including but not limited to BAM15 ((2-fluorophenyl){6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)}amine), a mitochondrial uncoupler, can improve glucose tolerance, increases cellular oxygen consumption, treat or prevent kidney ischemia reperfusion injury reverse insulin resistance, reverse or treat hyperinsulinemia, and reverse or treat hyperlipidemia. The present invention further provides novel compounds as well as methods for identifying compounds with the same or similar properties as BAM15.

## Claims

### Claim 1

A method of increasing oxygen consumption, reducing cellular reactive oxygen species, depolarizing a mitochondrial inner membrane, and increasing oxygen consumption rate without donating electrons to the electron transport chain using a mitochondrial uncoupler, said method comprising contacting a cell or mitochondria with a composition comprising at least one compound having a structure of formula I or formula II:
or active analogs or derivatives thereof,
wherein R1-R10 are all independently optional, and when present are each independently selected from the group consisting of H, halogen, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, and amino acid, wherein each group can be optionally substituted; or
or active analogs and derivatives thereof,
wherein R1-R2 are independently optional, and are each independently selected from the group consisting of H, halogen, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, and amino acid, wherein each group can be optionally substituted.

### Claim 2 (depends on 1)

The method of claim 1, further wherein said method increases extracellular acidification.

### Claim 3 (depends on 1)

The method of claim 1, wherein said compound is selected from the group consisting of:

### Claim 4 (depends on 1)

The method of claim 1, wherein said compound lacks protonophore activity at the cell membrane.

### Claim 5 (depends on 4)

The method of claim 4, wherein said compound is BAM15:

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is a mitochondrial uncoupler.

### Claim 7 (depends on 1)

The method of claim 1, where the compound is administered at a dosage ranging from about 1.0 mg/kg to about 50 mg/kg body weight.

### Claim 8 (depends on 1)

The method of claim 1, where the compound is administered at a dosage ranging from about 1.0 mg/kg to about 25 mg/kg body weight.

### Claim 9 (depends on 2)

The method of claim 2, where the compound is administered at a dosage ranging from about 1.0 mg/kg to about 5.0 mg/kg body weight.

### Claim 10 (depends on 1)

The method of claim 1, where the compound is administered at a dosage ranging from about 10 mg to about 500 mg.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound is administered more than once.