Compounds for modulating trpv3 function

Abstract

The present application relates to compounds and methods for treating pain and other conditions related to TRPV3.

1 . A method for treating or preventing a condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity, comprising administering an effective amount of a compound that inhibits TRPV3-mediated current with an IC 50  of 1 micromolar or less. 
     
     
         2 . The method of  claim 1 , wherein said compound inhibits at least 95% of TRPV3-mediated current at 5 micromolar or less. 
     
     
         3 . The method of  claim 1 , wherein said compound inhibits TRPV3 with an IC 50  at least one order of magnitude lower than its IC 50  for inhibition of one or more of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and hERG channel activities. 
     
     
         4 . The method of  claim 1 , wherein said compound inhibits TRPV3 with an IC 50  of 100 nanomolar or less. 
     
     
         5 . The method of  claim 1 , wherein the agent is an organic molecule having a molecular weight of 2000 amu or less. 
     
     
         6 . The method of  claim 1 , wherein the agent is administered topically. 
     
     
         7 . The method of  claim 1 , wherein the agent is administered orally. 
     
     
         8 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of acute pain, chronic pain, touch sensitivity, itching sensitivity, or as part of treating a burn. 
     
     
         9 . The method of  claim 8 , wherein the pain is post-surgical pain, cancer pain, or neuropathic pain. 
     
     
         10 . The method of  claim 1 , wherein the agent is administered transdermally, parenterally, rectally, vaginally, intranasally, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacly, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly, intraspinally, intrastemally or by inhalation. 
     
     
         11 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of migraine. 
     
     
         12 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of a disorder or condition selected from the group consisting of diabetic neuropathy, inflammation, Irritable Bowel Syndrome, Crohn's Disease, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), incontinence, bladder incontinence, bladder cystitis, fever, hot flashes, and cough. 
     
     
         13 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of osteoarthritis. 
     
     
         14 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of rheumatoid arthritis. 
     
     
         15 . The method of  claim 1 , used to prevent, treat or alleviate symptoms of oral mucositis. 
     
     
         16 . The method of  claim 1 , used as a depilatory to promote loss of or inhibit the growth of hair on a patient. 
     
     
         17 - 21 . (canceled) 
     
     
         22 . A method for treating or preventing a condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity, comprising administering an effective amount of a compound of Formula I or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar represents an aryl or heteroaryl group; 
 Y represents Ph, OArl, SArl, or N(U)(Arl), 
 R represents H or a lower alkyl; 
 X represents CH 2 , O, S, NR 10 , CF 2 , or C(CN) 2 ; 
 W represents O, S, or NR′; 
 n is 1, or when X is CH 2 , n is 1 or 2; 
 Arl represents an aralkyl, heteroaralkyl, aryl, or heteroaryl group, which may be monocyclic or bicyclic; 
 Ph represents a substituted or unsubstituted phenyl ring, optionally fused to a substituted or unsubstituted 5- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; 
 R′, independently for each occurrence, represents H or a lower alkyl; 
 U represents hydrogen or lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, 
 or, U, N and R′ taken together form a 5- to 7-membered heterocyclic ring, 
 or, U, Arl and N taken together form a ring fused to the aryl or heteroaryl ring of Arl, thereby forming a bicyclic structure; 
 R 10  represents H, lower alkyl, or cyano; and 
 
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         23 . The method of  claim 22 , wherein said compound is represented in Formula Ia, or is a salt, solvate, hydrate, oxidative metabolite or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar represents an aryl or heteroaryl group; 
 Y represents Ph, OArl, SArl, or N(U)(Arl), 
 R represents H or a lower alkyl; 
 X represents O, S, NR 10 , CF 2 , or C(CN) 2 ; 
 W represents O, S, or NR′; 
 Arl represents an aralkyl, heteroaralkyl, aryl, or heteroaryl group, which may be monocyclic or bicyclic; 
 Ph represents a substituted or unsubstituted phenyl ring, optionally fused to a substituted or unsubstituted 5- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; 
 R′, independently for each occurrence, represents H or a lower alkyl; 
 U represents hydrogen or lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, 
 or, U, N and R′ taken together form a 5- to 7-membered heterocyclic ring, 
 or, U, Arl and N taken together form a ring fused to the aryl or heteroaryl ring of Arl, thereby forming a bicyclic structure; 
 R 10  represents H, lower alkyl, or cyano; and 
 
       wherein said compound inhibits TRPV3 with an with an IC 50  of 10 micromolar or less. 
     
     
         24 . The method of  claim 23 , wherein Y is N(U)(Arl). 
     
     
         25 . The method of  claim 24 , wherein Y represents 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2 , each independently, is absent or represents one or more substituents on the ring to which it is attached; 
 Ar′ represents an aryl or heteroaryl group; 
 R 5  represents CH 2 , O, NR 6 ; 
 R 6  represents H or lower alkyl; and 
 n represents 1, 2, or 3. 
 
     
     
         26 - 70 . (canceled)