Compounds for modulating TRPV3 function

A compound of Formula IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:

• wherein
• R represents H, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
• R′ represents lower alkyl;
• L represents a linker selected from cis- or trans-ethene;
• and
• Ph represents a 2,3-, 2,4-, 2,5- or 2,6-disubstituted phenyl ring, wherein each substituent of the 2,3-, 2,4-, 2,5- or 2,6-disubstituted phenyl ring is independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, lower cycloalkyl, halogen, carbonyl, thiocarbonyl, ketone, aldehyde, hydroxy, alkoxy, acyloxy, amino, acylamino, amido, alkylsulfonyl, sulfamoyl, alkylsulfonamido, cyano, nitro, alkylthio, or azido, or Ph represents a monosubstituted 2-substituted phenyl ring, wherein the substituent of the monosubstituted 2-substituted phenyl ring is an electron withdrawing group, or Ph represents a 3,4-disubstituted phenyl ring, wherein each substituent of the 3,4-disubstituted phenyl ring is independently selected from substituted or unsubstituted alkyl or halogen, or Ph represents a monosubstituted 3-substituted phenyl ring, wherein the substituent of the monosubstituted 3-substituted phenyl ring is a substituted alkyl group or a lower alkyl group of two or more carbon atoms, or Ph represents a monosubstituted 4-substituted phenyl ring, wherein the substituent of the monosubstituted 4-substituted phenyl ring is a halogen.

A compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:

• wherein
• R represents H, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
• R′ represents lower alkyl;
• and
• Ph represents a substituted or unsubstituted phenyl ring.

A method for inhibiting a TRPV3 mediated current, comprising contacting a cell with an effective amount of a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:

• wherein
• Ar and Ar′ each independently represent an aryl or heteroaryl group;
• G1 and G2 each independently represent lower alkyl, or together with the carbons to which they are attached, G1 and G2 form an aryl or heteroaryl group fused to the pyrimidinone ring;
• L represents a linker having from 1-3 atoms;
• and
• wherein said compound inhibits a TRPV3 mediated current with an IC50 of 10 micromolar or less.

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 thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:

• wherein
• Ar and Ar′ each independently represent an aryl or heteroaryl group;
• G1 and G2 each independently represent lower alkyl, or together with the carbons to which they are attached, G1 and G2 form an aryl or heteroaryl group fused to the pyrimidinone ring;
• L represents a linker having from 1-3 atoms;
• and
• wherein said compound inhibits TRPV3 with an IC50 of 10 micromolar or less.

A method for treating pain, comprising administering an effective amount of a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:

• wherein
• Ar and Ar′ each independently represent an aryl or heteroaryl group;
• G1 and G2 each independently represent lower alkyl, or together with the carbons to which they are attached, G1 and G2 form an aryl or heteroaryl group fused to the pyrimidinone ring;
• L represents a linker having from 1-3 atoms;
• and
• wherein said compound inhibits TRPV3 with an IC50 of 10 micromolar or less. 1.5

Use in the treatment of pain of a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:

• wherein
• Ar and Ar′ each independently represent an aryl or heteroaryl group;
• G1 and G2 each independently represent lower alkyl, or together with the carbons to which they are attached, G1 and G2 form an aryl or heteroaryl group fused to the pyrimidinone ring;
• L represents a linker having from 1-3 atoms;
• and
• wherein said compound is a TRPV3 inhibitor that inhibits a TRPV3 mediated current with an with an IC50 of 10 micromolar or less.