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Small molecule dual-inhibitors of trpv4 and trpa1 for sanitizing and anesthetizing

A technology of inhibitors and anesthetics, applied in the field of small molecule dual inhibitors of TRPV4 and TRPA1 for disinfection and anesthesia, which can solve the problems of not knowing or not knowing the specific inhibitors of TRPV4 and TRPA1

Inactive Publication Date: 2019-02-05
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although TRPV4 and TRPA1 play a role in the skin, it is unknown whether targeting TRPV4 and / or TRPA1 will have a role in the treatment of inflammation, pain, itching, cancer, autoimmune disease, fibrotic disease, skin pigmentation and other skin disorders Useful in
Furthermore, no specific inhibitors of TRPV4 and TRPA1 are currently known

Method used

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  • Small molecule dual-inhibitors of trpv4 and trpa1 for sanitizing and anesthetizing
  • Small molecule dual-inhibitors of trpv4 and trpa1 for sanitizing and anesthetizing
  • Small molecule dual-inhibitors of trpv4 and trpa1 for sanitizing and anesthetizing

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0206] Example 1: Materials and methods

[0207] animal. The genomic locus of Trpv4 was engineered such that a loxP site surrounds exon 13 encoding TM5-6. This mutation is transmitted in mice crossed with K14-CRE-ERtam mice, allowing ((Trpv4lox / lox)X(K14-CRE-ERtam)) mice to be administered by oral gavage at 2-4 months of age in Tamoxifen in 0.3 mL corn oil was administered at a dose of 6 mg / day for 5 consecutive days plus a booster at 2 weeks after the last dose for induction. Male and female mice were equally induced. The efficiency of knockdown was verified by qRT-PCR on Trpv4 using the sense primer 5'-CCTGCTGGTCACCTACATCA (SEQ ID NO:1) and the antisense primer 5'-CTCAGGAACACAGGGAAGGA (SEQ ID NO:2), where the former primer was located outside Exon 13. All animal experiments described here were performed in full compliance with NIH and Duke University internal guidelines and under legitimate IACUC protocols.

[0208] Using the same genomic clone used to generate Trpv4- / -...

Embodiment 2

[0252] Example 2: Generation of epidermis-specific, tamoxifen-inducible Trpv4-null mice

[0253] To overcome developmental issues that may arise in gene-targeted mice with ubiquitous deletions, we developed an inducible conditional system to assess the role of TRPV4 in UVB-mediated skin irritation, inflammation, and sensory sensitization. Using mouse ES cells, we first established Trpv4lox / lox mice such that the size-tunable exons encoding transmembrane domains 5, 6 and the intervening pore loop are flanked by loxP elements. After crossing with FLPe mice to remove selection markers flanked by frt elements, these animals were treated with tamoxifen (tam) inducible keratin-14 (K14)-CRE ER Transgenic mice were mated. An overview of constructs and genotyping is at Figure 1A -B in.

[0254] We focused our analysis on the paw pad skin of adult (2 month old) glandular mice as it more closely resembles human skin. Tamoxifen induction caused a highly efficient knockdown of Trpv4 e...

Embodiment 3

[0256] Example 3: Pain response behavior induced by UVB exposure is dependent on epidermally expressed TRPV4

[0257] Underscored the specificity of Trpv4 gene targeting, so that footpad-innervated peripheral sensory neurons still showed robust TRPV4 expression ( Figure 1D ). This allowed us to assess whether epidermal Trpv4 deficiency critically affects UVB-mediated pain response behavior. For this purpose, we analyzed two relevant sub-modalities - thermal and mechanical stimulation - and compared our iKO mice with full deletion Trpv4- / - and their wild-type (WT) controls ( Figure 3B ). At 48 hours after UV exposure, both tam-treated iKO and Trpv4- / - mice exhibited greater response to noxious radiant heat (Hargreaves test) as well as noxious mechanical stimulation (using automated von Frey hair test) much lower sensitivity. We conclude that epidermis-specific TRPV4 deficiency is equivalent to global TrpV4 ablation in reducing UVB-induced behavioral sensitization to radia...

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Abstract

Provided are methods of sanitizing a subject, and methods of anesthetizing a subject. Further provided are methods of treating and / or preventing dermatological disorders, 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.

Description

[0001] Cross references to related applications [0002] This application claims U.S. Provisional Patent Application No. 62 / 319,684, filed April 7, 2016, U.S. Provisional Patent Application No. 62 / 331,951, filed May 4, 2016, and U.S. Provisional Patent Application No. 6, filed May 17, 2016 62 / 337,701 priority, each of which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Funded Research [0004] This invention was made under grant numbers DE018549 and DE018529S1 awarded by the National Institutes of Health / National Institute of Dental and Craniofacial Research (NIH / NIDCR) and by the National Institutes of Health / National Institute of Dental and Craniofacial Research Made with government support under grant numbers AR059402, AR31737 and AR050452 awarded by the National Institutes of Health / National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH / NIAMS). The US Government has certain rights in this invention. techni...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61K31/426
CPCA61K45/06A61K31/4439A61K33/18A61K31/426A61P29/02A61K2300/00
Inventor 沃尔夫冈·利特克
Owner DUKE UNIV
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