Activation of trpv4 ion channel by physical stimuli and critical role for trpv4 in organ-specific inflammation and itch

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.

1 - 25 . (canceled) 
     
     
         26 . The TRPV4 inhibitor of  claim 27 , wherein the compound is selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         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 C 1 -C 3  alkylene; 
         E is a bond, or C 1 -C 2  alkylene; and 
         R is selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, alkenyl, heteroalkyl, aromatic ring, or heteroaromatic ring. 
       
     
     
         28 . The TRPV4 inhibitor of  claim 27 , wherein A is phenyl or heteroaryl. 
     
     
         29 . The TRPV4 inhibitor of  claim 28 , wherein A is heteroaryl. 
     
     
         30 . The TRPV4 inhibitor of  claim 28 , wherein A is phenyl. 
     
     
         31 . The TRPV4 inhibitor of  claim 27 , wherein A is pyridnyl. 
     
     
         32 . The TRPV4 inhibitor of  claim 27 , wherein B is a phenyl group. 
     
     
         33 . The TRPV4 inhibitor of  claim 27 , wherein C is a phenyl group. 
     
     
         34 . The TRPV4 inhibitor of  claim 27 , wherein D is ethylene. 
     
     
         35 . The TRPV4 inhibitor of  claim 27 , wherein E is methylene. 
     
     
         36 . The TRPV4 inhibitor of  claim 27 , wherein R is C1-C4 alkyl. 
     
     
         37 . The TRPV4 inhibitor of  claim 35 , wherein R is methyl. 
     
     
         38 . The TRPV4 inhibitor of  claim 35 , wherein R is ethyl. 
     
     
         39 . 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. 
     
     
         40 . 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. 
     
     
         41 . A topical formulation comprising a TRPV4 inhibitor according to  claim 27 .