# US 2018/0022740 A1 · Activation of trpv4 ion channel by physical stimuli and critical role for trpv4 in organ-specific inflammation and itch

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- Number: US 2018/0022740 A1
- Document ID: US20180022740A1
- Status: Published application
- Kind: A1
- Application number: 15/624,508
- Filed: 2017-06-15
- Published: 2018-01-25
- Earliest claimed: 2012-07-06
- Assignees: Duke University; The Regents of the University of California
- Applicants: Duke University; The Regents of the University of California
- Inventors: Wolfgang Liedtke; Martin Steinhoff; Farshid Guilak
- Web page: https://patentgrep.com/patent/US20180022740A1

## CPC

- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- 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 31/4439: 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}
- A61P 17/00: Drugs for dermatological disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- 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 2267/03: Animal model, e.g. for test or diseases
- A01K 2267/0356: Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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 TRPV4 inhibitor. Further provided are compositions including a TRPV4 inhibitor compound in combination with a carrier, vehicle, or diluent that is suitable for topical application. Further provided is a transgenic mouse whose genome includes deletions of the Trpv4 gene in keratinocytes of the epidermis, wherein said transgenic mouse is a knockout for the Trpv4 gene in keratinocytes of the epidermis following keratinocyte-specific activation and expression of a site-specific recombination enzyme.

## Claims

### Claim at position 1

1-25. (canceled)

### Claim 26 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein the compound is selected from the following:

### Claim 27

A TRPV4 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 28 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein A is phenyl or heteroaryl.

### Claim 29 (depends on 28)

The TRPV4 inhibitor of claim 28, wherein A is heteroaryl.

### Claim 30 (depends on 28)

The TRPV4 inhibitor of claim 28, wherein A is phenyl.

### Claim 31 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein A is pyridnyl.

### Claim 32 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein B is a phenyl group.

### Claim 33 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein C is a phenyl group.

### Claim 34 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein D is ethylene.

### Claim 35 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein E is methylene.

### Claim 36 (depends on 27)

The TRPV4 inhibitor of claim 27, wherein R is C1-C4 alkyl.

### Claim 37 (depends on 35)

The TRPV4 inhibitor of claim 35, wherein R is methyl.

### Claim 38 (depends on 35)

The TRPV4 inhibitor of claim 35, wherein R is ethyl.

### Claim 39 (depends on 35)

The TRPV4 inhibitor of claim 35, wherein A is heteroaryl, B and C are phenyl, D is ethylene, E is methylene, and R is methyl.

### Claim 40 (depends on 27)

A composition comprising a TRPV4 inhibitor compound according to claim 27 in combination with a carrier, vehicle, or diluent, that is suitable for topical application.

### Claim 41 (depends on 27)

A topical formulation comprising a TRPV4 inhibitor according to claim 27.