# US 2019/0315700 A1 · Trpa1 and trpv4 inhibitors and methods of using the same for organ-specific inflammation and itch

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- Number: US 2019/0315700 A1
- Document ID: US20190315700A1
- Status: Published application
- Kind: A1
- Application number: 16/391,047
- Filed: 2019-04-22
- Published: 2019-10-17
- Earliest claimed: 2017-02-22
- Assignees: Duke University
- Applicants: Duke University
- Inventors: Wolfgang Liedtke; Farshid Guilak
- Web page: https://patentgrep.com/patent/US20190315700A1

## CPC

- C07D 277/20: having two or three double bonds between ring members or between ring members and non-ring members
- A01K 67/0276: Knock-out vertebrates
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 31/426: 1,3-Thiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 49/0008: {Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure}
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- G01N 33/6881: {from skin}
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2217/206: Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
- A01K 2227/105: Murine
- A01K 2267/0356: Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
- A01K 2267/0368: Animal model for inflammation
- G01N 2333/4703: Regulators; Modulating activity
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2500/10: involving cells
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- 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)
- 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

Provided are methods of treating and/or preventing dermatological disorders. Provided are methods of reducing skin inflammation, reducing pain, and/or reducing itch in a subject in need thereof. The methods may include administering to the subject an effective amount of a TRPA1 and/or TRPV4 inhibitor. Further provided are compositions including a TRPA1 and/or TRPV4 inhibitor compound in combination with a carrier, vehicle, or diluent that is suitable for topical application.

## Claims

### Claim 1

A TRPV4 and TRPA1 inhibitor comprising a compound according to Formula I:
wherein A, B, and C are independently selected from the group consisting of aromatic, heteroaromatic, cycloalkenyl, and heterocycloalkenyl groups;
D is C1-C3 alkylene;
E is a bond, or C1-C2 alkylene; and
R is selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, alkenyl, heteroalkyl, aromatic ring, or heteroaromatic ring.

### Claim 2 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein the compound does not inhibit TRPV1, TRPV2, or TRPV3.

### Claim 3 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein A is selected from phenyl and pyridnyl.

### Claim 4 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein A is phenyl.

### Claim 5 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein A is pyridnyl.

### Claim 6 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein B and C are phenyl.

### Claim 7 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein D is ethylene.

### Claim 8 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein E is C1-C2 alkylene.

### Claim 9 (depends on 8)

The TRPV4 and TRPA1 inhibitor of claim 8, wherein E is methylene.

### Claim 10 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein R is selected from hydrogen, hydroxyl, amino, alkyl, and alkenyl.

### Claim 11 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein R is C1-C4 alkyl.

### Claim 12 (depends on 11)

The TRPV4 and TRPA1 inhibitor of claim 11, wherein R is methyl.

### Claim 13 (depends on 11)

The TRPV4 and TRPA1 inhibitor of claim 11, wherein R is ethyl.

### Claim 14 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein A and B and C are phenyl, D is ethylene, E is methylene, and R is methyl.

### Claim 15 (depends on 1)

The TRPV4 and TRPA1 inhibitor of claim 1, wherein the TRPV4 and TRPA1 inhibitor comprises a compound selected from the following:

### Claim 16 (depends on 1)

A composition comprising the TRPV4 and TRPA1 inhibitor of claim 1 in combination with a carrier, vehicle, or diluent, that is suitable for topical application.