Compounds for modulating TRPV3 function

BACKGROUND

A variety of ion channel proteins exist to mediate ion flux across cellular membranes. The proper expression and function of ion channel proteins is essential for the maintenance of cell function, intracellular communication, and the like. Numerous diseases are the result of misregulation of membrane potential or aberrant calcium handling. Given the central importance of ion channels in modulating membrane potential and ion flux in cells, identification of agents that can promote or inhibit particular ion channels are of great interest as research tools and as possible therapeutic agents.

One such channel is the Transient Receptor Potential V3 (TRPV3) channel. TRPV3 is a calcium permeable channel, specifically a calcium permeable non-selective cation channel. In addition to calcium ions, TRPV3 channels are permeable to other cations, for example sodium. Thus, TRPV3 channels modulate membrane potential by modulating the flux of cations such as calcium and sodium ions. Although non-selective cation channels such as TRPV3 modulate, among other things, calcium ion flux, they are mechanistically distinct from voltage-gated calcium channels. Generally, voltage-gated calcium channels respond to membrane depolarization and open to permit an influx of calcium from the extracellular medium that results in an increase in intracellular calcium levels or concentrations. In contrast, TRP channels which are non-selective cation channels are generally signal transduction gated, long lasting, and produce more prolonged changes in ion concentration. These mechanistic differences are accompanied by structural differences among voltage-gated and TRP channels. Thus, although many diverse channels act to regulate ion flux and membrane potential in various cell types and in response to numerous stimuli, it is important to recognize the significant structural, functional, and mechanistic differences among different classes of ion channels.

TRPV3 function has been implicated in, among other things, the reception and transduction of pain. Accordingly, it would be desirable to identify and make compounds that can modulate one or more functions of TRPV3. Such compounds have a variety of in vitro and in vivo uses.

SUMMARY

An important aspect of achieving cellular homeostasis is the maintenance of appropriate ion concentrations in various cell types during the development of and in response to numerous stimuli. Large numbers of diverse types of ion channels act to maintain cellular homeostasis by moving ions into and out of cells across the plasma membrane, and within cells by moving ions across membranes of intracellular organelles including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria and endocytic organelles including endosomes and lysosomes. One such ion channel is the non-selective cation channel TRPV3. TRPV3 is cation permeable and belongs to the larger family of TRP ion channels.

TRP channels have been classified into at least six groups: TRPC (short), TRPV (vanilloid), TRPM (long, melastatin), TRPP (polycystins), TRPML (mucolipins), and TRPA (ANKTM1). The TRPC group can be divided into 4 subfamilies (TRPC1, TRPC4,5, TRPC3,6,7 and TRPC2) based on sequence homology and functional similarities. Currently the TRPV family has 6 members. TRPV5 and TRPV6 are more closely related to each other than to TRPV1, TRPV2, TRPV3, or TRPV4. TRPV3 is most closely related to TRPV4, and is more closely related to TRPV1 and TRPV2 than to TRPV5 and TRPV6. The TRPM family has 8 members. Constituents include the following: the founding member TRPM1 (Melastatin or LTRPC1), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(1), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (Trp-p8 or CMR1), TRPM5 (Mtr1 or LTRPC5), and TRPM4 (FLJ20041 or LTRPC4). The sole mammalian member of the TRPA family is ANKTM1. The TRPML family consists of the mucolipins, which include TRPML1 (mucolipins 1), TRPML2 (mucolipins 2), and TRPML3 (mucolipin3). The TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have 11. TRPP2 (PKD2), TRPP3 (PKD2L1), TRPP5 (PKD2L2) are all predicted to have six transmembrane domains. TRPP1 (PKD1, PC1), PKD-REJ and PKD-1L1 are all thought to have 11 transmembrane domains.

The TRP channels constitute a large and important class of channels involved in modulating cellular homeostasis. The present invention provides methods and compositions that modulate at least one TRP family member. Specifically, the present invention provides methods and compositions for antagonizing a function of TRPV3. Modulating a function of TRPV3 provides a means for modulating calcium homeostasis, sodium homeostasis, intracellular calcium levels, membrane polarization (resting membrane potential), and/or cation levels in a cell. Compounds that can modulate one or more TRPV3 functions are useful in many aspects including, but not limited to, maintaining calcium homeostasis; maintaining sodium homeostasis; modulating intracellular calcium levels; modulating membrane polarization (membrane potential); modulating cation levels; and/or treating or preventing diseases, disorders, or conditions associated with calcium homeostasis, sodium homeostasis, calcium or sodium dyshomeostasis, or membrane polarization/hyperpolarization (including hypo and hyperexcitability), and/or treating or preventing diseases, disorders, or conditions associated with regulation or misregulation of TRPV3 expression or function. Additionally, the present invention provides, in certain embodiments, methods and compositions that antagonize both a function of TRPV3 and a function of one or more additional TRP channels.

The present application provides compounds that can modulate TRPV3 function. Methods employing these compounds are also provided. Certain embodiments provide a method of modulating a TRPV3 function in a cell comprising administering to the cell an effective amount of a compound that inhibits a TRPV3 mediated current. Certain embodiments provide a method of modulating a TRPV3 function in a cell comprising administering to the cell an effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase II outward current mediated by TRPV3. Certain embodiments provide a method of preventing or treating a disease or condition related to TRPV3 function in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase II outward current mediated by TRPV3. Certain embodiments provide a method of modulating a TRPV3 function in a cell comprising administering to the cell an effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase II inward current mediated by TRPV3. Certain embodiments also provide a method of preventing or treating a disease or condition related to TRPV3 function in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase II inward current mediated by TRPV3. Certain embodiments provide a method of modulating TRPV3 function in a cell comprising administering to the cell an effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase I inward current mediated by TRPV3. Certain embodiments also provide a method of preventing or treating a disease or condition related to TRPV3 function in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase I inward current mediated by TRPV3. Certain embodiments also provide a method of preventing or treating a disease or condition related to TRPV3 function in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase I outward current mediated by TRPV3. Certain embodiments provide a method of modulating TRPV3 function in a cell comprising administering to the cell an effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits the Phase I outward current mediated by TRPV3. Certain embodiments also provide a method of preventing or treating a disease or condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits TRPV3 function, wherein the compound inhibits one or more of a Phase I inward current mediated by TRPV3, a Phase II inward current mediated by TRPV3, a Phase I outward current mediated by TRPV3, or a Phase II outward current mediated by TRPV3. In any of the foregoing, the invention additionally provides compounds and methods that inhibit both the Phase I outward current and the Phase II outward current. Furthermore, in any of the foregoing, the invention provides compounds and methods that inhibit both the Phase I inward current and the Phase II inward current, as well as compounds that inhibit any combination of Phase I and Phase II currents. Note that inhibition of a particular current refers to the ability of a compound to inhibit that current (e.g., Phase I inward, Phase I outward, Phase II inward, and/or Phase II outward) in either an in vitro or in vivo assay. Inhibition of a particular current in either an in vivo or an in vitro assay serves as a proxy for the particular functional activity of the particular compound.

The biphasic currents mediated by TRPV3 are discussed in, for example, Chung et al. (Chung et al., 2005, Journal of Biological Chemistry 280: 15928-15941). Briefly, a unique property of TRPV3 is that there is a phase change in the current. The current-voltage relationship changes upon repeated stimulation, so that the amount of inward current increases dramatically. For ease, two phases of TRPV3 current have been described: Phase I and Phase II. Throughout, we have defined phase I as currents that show a 10:1 ratio or greater of outward current amplitude (at +100 mV) to inward current amplitude (at −120 mV). In other words, the current shows strong outward rectification and minimal inward current. Phase II is defined as a ration of 2:1 or less of outward current amplitude (at +100 mV) to inward current amplitude (at −120 mV). The current-voltage relationship is fairly linear in this case.

The following articles are exemplary of the state of the art regarding the structure and function of TRPV3 (Ramsey et al. (2006) Annual Rev Physiology 68: 619-647; Clapham. (2003) Nature 426: 517-524; Xu et al. (2002) Nature 418: 181-186; Clapham et al. (2001) Nature Reviews of Neuroscience 2: 387-396). The foregoing articles are incorporated by reference in their entirety.

One aspect of the present invention relates to a method for treating or preventing a condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity by administering a TRPV3 antagonist that inhibits TRPV3-mediated current. Described in greater detail below are TRPV3 antagonists that have measured IC₅₀'s for inhibition of TRPV3 of 10 micromolar or less, 1 micromolar or less, 500 nanomolar or less, 200 nanomolar or less, 100 nanomolar or less, and even 10 nanomolar or less. In certain embodiments, the TRPV3 antagonist inhibit one or both of inward and outward TRPV3-mediated current with an IC₅₀of 1 micromolar or less, and more with an IC₅₀of 500 nanomolar or less, 200 nanomolar or less, 100 nanomolar or less, 25 nanomolar or less and even 10 nanomolar or less. In certain embodiments, the TRPV3 antagonist inhibits at least 95% of TRPV3-mediated current at 5 micromolar or less, and even more preferably at 1 micromolar or less.

In certain embodiments, the subject TRPV3 antagonists inhibit TRPV3 with an IC₅₀at least one order of magnitude lower than its IC₅₀for inhibition of one or more of TRPV5, TRPV6, NaV 1.2, TRPV1, mitochondrial uniporter and hERG channel activities, and even more preferably two or even three orders of magnitude lower.

In certain embodiments, the TRPV3 antagonists inhibit TRPV3 with an IC₅₀at least one order of magnitude lower than its IC₅₀for inhibition of TRPV1, and even more preferably two or even three orders of magnitude lower. In certain embodiments, the subject TRPV3 antagonists can be selected for selectivity for TRPV3 versus TRPV1 on the basis of having IC₅₀for TRPV1 inhibition greater than 10 micromolar.

In certain embodiments, the TRPV3 antagonists inhibit one or more of TRPV2, TRPV4, ANKTM1 and/or TRPM8 with an IC₅₀of 10 micromolar or less.

In certain embodiments, the TRPV3 antagonist has a therapeutic index (T.I.) for treating the condition with the compound of 10 or greater, and even more preferably has a T.I. of at least 25, 50 or even 100.

In preferred embodiments, the TRPV3 inhibitor has an IC₅₀for TRPV3 inhibition that, at that concentration, does not cause QT interval elongation in the patient nor alter temperature regulation in the patient.

In certain embodiments, the TRPV3 inhibitor is used to treat or ameliorate pain. Exemplary classes of pain that can treated using a TRPV3 inhibitor include, but are not limited to nociceptive pain, inflammatory pain, and neuropathic pain. Pain that can be treated with a TRPV3 inhibitor can be chronic or acute.

In certain embodiments, the TRPV3 inhibitor is non-narcotic and has little or no narcotic side-effects. In certain other embodiments, the TRPV3 inhibitor can be used to treat or ameliorate pain with fewer side-effects than narcotic pain relievers. Exemplary side-effects that may be substantially absent at effective dosages of TRPV3 inhibitors include one or more of exopthalmos, catalepsy, disruption of gut motility, and inhibiton of sensation in non-injured areas of the body.

In certain embodiments, the TRPV3 antagonist is “small molecule”, e.g., an organic molecule having a molecular weight of 2000 amu or less. Exemplary TRPV3 antagonists include a compound of Formula I or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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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 CH₂, O, S, NR₁₀, CF₂, or C(CN)₂; W represents O, S, or NR′; n is 1, or when X is CH₂, 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; R₁₀represents H, lower alkyl, or cyano; and wherein said compound inhibits TRPV3 with an with an IC₅₀of 10 micromolar or less.

In certain embodiments, R is H, W is O or S, and X is O or S.

In certain embodiments, X is CH₂.

In certain preferred embodiments, the TRPV3 antagonist is represented in Formula Ia, or is a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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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, NR₁₀, CF₂, 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; and R₁₀represents H, lower alkyl, or cyano.

In certain embodiments of Formulas I and Ia, Y is N(U)(Arl), and in such embodiments, Y can represent, for example,

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wherein: R₁and R₂, 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; R₅represents CH₂, O, NR₆; R₆represents H or lower alkyl; and n represents 1, 2, or 3. In certain embodiments of the above-referenced compounds, one or more of the following conditions may be true:

- Ar′ represents phenyl, thiophene, imidazole, thiazole, furan, oxazole, tetrazole, thiadiazole, pyridine, pyrimadine, or triazole;
- each R₁is independently selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl;
- each R2 is independently selected from H, lower alkyl, alkoxy, carboxyl, ester amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano;

In certain preferred embodiments of Formulas I and Ia, Y represents

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wherein R₁and R₂each, independently, are absent or represent one or more substituents on the ring to which they are attached. Even more preferably, independently for each occurrence, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R1 taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and independently for each occurrence, R₂is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

For further illustration, Y can represent

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wherein R₁represents H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂represents H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano. In certain preferred embodiments, R₁represents H, lower alkyl, alkoxy, or R₁taken together with the carbon to which it is attached forms a carbonyl, and R₂represents H, lower alkyl, alkoxy or halogen.

In certain preferred embodiments of Formulas I and Ia, Ar represents

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wherein: Cy represents an aryl or heteroaryl ring; Z represents O, S, NR₁₁, CF₂, or C(CN)₂; R₃is absent or represents one or more substituents on the ring to which it is attached; R₁₁represents H, lower alkyl, or cyano; A represents N or C(R_2a); and R_2arepresents H, lower alkyl, alkoxy, or halogen.

For example, Cy can represent a phenyl, thiophene, imidazole, thiazole, furan, oxazole, tetrazole, thiadiazole, pyridine, pyrimadine, or triazole, and R₃can be absent, or independently for each occurrence, selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano. In certain preferred embodiments, A represents N, and Z represents O or S.

To further illustrate, Ar can represent

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wherein: Z represents O, S, NR₁₁, CF₂, NR, or C(CN)₂; A represents N or C(R_2a); R₃is absent or represents one or more substituents on the ring to which it is attached; R₁₁represents H, lower alkyl, or cyano; and R_2arepresents H, lower alkyl, alkoxy, or halogen. In certain preferred embodiments: Z represents O or S; and R₃is absent or each R₃is independently selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano;

In certain preferred embodiments, Ar can represent

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wherein: Z represents O, S, NR₁₁, CF₂, or C(CN)₂; A represents N or C(R_2a); R₃independently for each occurrence represents H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano; R₁₁represents H, lower alkyl, or cyano; and R_2arepresents H, lower alkyl, alkoxy, or halogen. Preferrably Z represents O or S, and R₃independently for each occurrence represents H, lower alkyl, alkoxy, CF₃, nitro, or halogen.

In certain other preferred embodiments of Formulas I and Ia, Ar represents

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wherein: G′ represents N or C(R₅); R₃is absent or represents one or more substituents on Cy; R₅represents H or a substituent; R₄represents H or a substituent; and Cy represents an aryl or heteroaryl ring. In certain preferred embodiments, Cy can be a phenyl, thiophene, imidazole, thiazole, furan, oxazole, tetrazole, thiadiazole, pyridine, pyrimadine, or triazole. In certain embodiments, R₃is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano; and R₄and R₅, independently for each occurrence, are selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

In still other embodiments, the TRPV3 antagonist is a compound of Formula V or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: X represents O, S, NR₁₀, CF₂, or C(CN)₂; Z represents O, S, NR₁₁, CF₂, or C(CN)₂; R₁₀represents H, lower alkyl, or cyano; R₁₁represents H, lower alkyl, or cyano; A represents N or C(R₂); G represents N or C(R₃); R₁is absent or represents one or more substituents on the ring to which it is attached; R₂represents, independently for each occurrence, H or a substituent; R₃represents, independently for each occurrence, H or a substituent; and D represents O or N.

In certain preferred embodiments of formula V: X represents S and D represents O; R₁is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃, independently for each occurrence, are selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano.

To further illustrate, the TRPV3 antagonist can be represented by Formula Va:

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wherein: R₁, R₂and R₃are absent or represent one or more substituents on the ring to which they are attached. For instance, R₁is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃are absent, or independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano. In certain preferred embodiments, R₁is absent, or independently for each occurrence, is selected from lower alkyl, or alkoxy, or R₁taken together with the carbon to which it is attached forms a carbonyl; R₂is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, or halogen; and R₃is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, CF₃, nitro, or halogen. In even more preferred embodiments, R₁represents H; R₂represents H or CH₃and is positioned ortho to the N of the ring system; and R₃represents one or more substituents positioned meta or para to the nitrogen of the ring system.

In still another illustration, the TRPV3 antagonist can be represented by Formula Vb:

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wherein R₁, R₂and R₃are absent or represent one or more substituents on the ring to which they are attached. For instance, R₁is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃are absent, or independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano. In certain preferred embodiments, R₁is absent, or independently for each occurrence, is selected from lower alkyl, or alkoxy, or R₁taken together with the carbon to which it is attached forms a carbonyl; R₂is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, or halogen; and R₃is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, CF₃, nitro, or halogen. In certain embodiments, R₁, R₂, and R₃are absent.

In still other embodiments, the TRPV3 antagonist is a compound of Formula VI or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: X represents O, S, NR₁₀, CF₂, or C(CN)₂; R₁₀represents H, lower alkyl, or cyano; A represents N or C(R₂); G represents N or C(R₃); R₁is absent or represents one or more substituents on the ring to which it is attached; R₂represents, independently for each occurrence, H or a substituent; R₃represents, independently for each occurrence, H or a substituent; R₄represents H or a substituent; D represents O or N; and wherein said compound inhibits TRPV3 with an with an IC₅₀of 10 micromolar or less.

In certain preferred embodiments, X represents S and D represents O.

In certain embodiments, the compound can be represented by Formula VIa:

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wherein: R₁, R₂and R₃are absent or represent one or more substituents on the ring to which they are attached; and R₄represents H or a substituent. In certain preferred embodiments, R₁is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂, R₃and R₄are absent, or independently for each occurrence, is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano. In preferred embodiments, the R₁is absent, or independently for each occurrence, is selected from lower alkyl, or alkoxy, or R₁taken together with the carbon to which it is attached forms a carbonyl; R₂is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, or halogen; R₃absent, or independently for each occurrence, is selected from H, lower alkyl, alkoxy, CF₃, nitro, or halogen; and R₄is selected from H, lower alkyl, or cyano. In other preferred embodiments, R₁and R₂are absent; R₃represents methoxy positioned para to the N of the ring system; and R₄represents cyano.

In certain embodiments, the compound can be represented by Formula VIb:

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wherein: R₁, R₂and R₃are absent or represent one or more substituents on the ring to which they are attached; and R₄represents H or a substituent. For instance, R₁is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂, R₃and R₄are absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano. In certain preferred embodiments, R₁is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, or halogen or R₁taken together with the carbon to which it is attached forms a carbonyl; R₂is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, or halogen; R₃is absent, or independently for each occurrence, is selected from lower alkyl, alkoxy, CF₃, nitro, or halogen; and R₄is selected from H, lower alkyl, or cyano.

In still other illustrative embodiments, the compound can be represented by Formula II or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: W represents O or S; X′ represents NR₁₂; R₁₂represents H or lower alkyl; Ar and Ar′ independently represent substituted or unsubstituted aryl or heteroaryl rings; and wherein said compound inhibits TRPV3 with an with an IC₅₀of 10 micromolar or less. For instance, Ar can represents phenyl, as can Ar′.

In yet another illustrative embodiments, the compound can be represented by Formula III or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: Ar represents a substituted or unsubstituted aryl or heteroaryl ring; Q represents O, S, NR, or CH₂; R, independently for each occurrence, represents H or lower alkyl; R′ represents H or a substituted or unsubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl; R″, independently for each occurrence, represents H or lower alkyl; V is absent or represents C═O, C═S, or SO₂; W represents a hydrogen-bond acceptor, such as ═O, ═S, amino, hydroxyl, or ether; E represents H, a substituted or unsubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, or halogen, carbonyl (e.g., ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, or phosphoryl; x represents 0 or 1 wherein when x is 0, the carbons bearing W and V are directly linked by a single or double bond; and wherein said compound inhibits TRPV3 with an with an IC₅₀of 10 micromolar or less.

In certain embodiments, the compounds of Formula III are characterized by one or more of the following: Q represents S or CH₂; R represents H; R′ represents a substituted or unsubstituted aryl or heteroaryl ring; R″ represents lower alkyl; and/or E represents CO₂Me or CO₂Et.

Additional illustrative embodiments of TRPV3 antagonists include compounds can be represented by Formula IV or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: Ar and Ar′ independently represent substituted or unsubstituted aryl or heteroaryl rings; R, independently for each occurrence, represents H or lower alkyl; X, independently for each occurrence, represents O, S, NR, CF₂, or CR₂; M, independently for each occurrence, represents a substituted or unsubstituted methylene group; and wherein said compound inhibits TRPV3 with an with an IC₅₀of 10 micromolar or less. For instance

In certain embodiments, the compounds of Formula IV are characterized by one or more of the following: Ar and Ar′ represent phenyl or pyridyl rings; R represents H; X represents O or S; M represents CH₂.

The TRPV3 antagonist of the subject invention can be used as part of a prophylaxis or treatment for a variety of disorders and conditions, including, but not limited to, acute and/or chronic pain, touch sensitivity, burns, inflammation, diabetic neuropathy, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), migraine, incontinence, fever, hot flashes, osteoarthritis, oral mucositis, cancer pain, bladder cystits, pain associated with Crohn's disease and Irritable Bowel Syndrome (IBS), rheumatoid arthritis, Grierson-Gopalan syndrome (better known as burning feet syndrome), burning mouth syndrome (BMS) and cough, or is used as a depilatory to promote loss of or inhibit the growth of hair on a patient.

The TRPV3 antagonists can be administered alone or in combination with other therapeutic agents. For instance, the TRPV3 antagonists is administered conjointly with one more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, anti-fungal agent, anti-viral agent, anti-septic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor.

The TRPV3 antagonists can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacly, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly, intraspinally, intrasternally or by inhallation.

In certain preferred embodiments, the TRPV3 antagonists is administered topically.

In certain preferred embodiments, the TRPV3 antagonists is administered orally.

In certain preferred embodiments, the TRPV3 antagonists is administered parenterally.

In certain preferred embodiments, the TRPV3 antagonists is administered to prevent, treat or alleviate signs and symptoms of acute pain, chronic pain, touch sensitivity, itching sensitivity, or as part of treating a burn, such as, for example, post-surgical pain, cancer pain, or neuropathic pain.

In certain preferred embodiments, the TRPV3 antagonists is administered to prevent, treat or alleviate signs and symptoms of migraine.

In certain preferred embodiments, the TRPV3 antagonists is administered to prevent, treat or alleviate signs and symptoms of a disorder or condition selected from the group consisting of diabetic neuropathy, inflammation, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), incontinence, bladder incontinence, fever, hot flashes, and cough.

In certain preferred embodiments, the TRPV3 antagonists is administered to prevent, treat or alleviate signs and symptoms of osteoarthritis.

In certain preferred embodiments, the TRPV3 antagonists is administered to prevent, treat or alleviate signs and symptoms of rheumatoid arthritis.

In certain preferred embodiments, the TRPV3 antagonists is administered to prevent, treat or alleviate signs and symptoms of oral mucositis.

In certain preferred embodiments, the TRPV3 antagonists is administered to promote loss of or inhibit the growth of hair on a patient.

Still another aspect of the present invention relates to the use of a TRPV3 antagonist, e.g., a small molecule agent that inhibits inward TRPV3-mediated current with an IC₅₀of 1 micromolar or less, in the manufacture of a medicament to prevent, treat or alleviate symptoms of a disease, disorder or condition involving activation of TRPV3, or for which reduced TRPV3 activity can reduce the severity, in a patient.

Yet another aspect of the present invention relates to a pharmaceutical preparation comprising an agent that inhibits inward TRPV3-mediated current with an IC₅₀of 1 micromolar or less; and a pharmaceutically acceptable excipient or solvent wherein the agent is provided in a dosage form providing an amount effective to prevent, treat or alleviate symptoms of a disease, disorder or condition involving activation of TRPV3, or for which reduced TRPV3 activity can reduce the severity, in a patient. In certain preferred embodiments, the pharmaceutical preparation does not cause QT interval elongation in the patient.

In certain illustrative embodiments, the pharmaceutical preparation comprises an agent that inhibits TRPV3-mediated current with an IC₅₀of at least one order of magnitude lower than its IC₅₀for inhibition of NaV 1.2 function, TRPV1 function, TRPV5 function, TRPV6 function, mitochondrial uniporter function and HERG function; and a pharmaceutically acceptable excipient or solvent, wherein the agent is provided in a dosage form providing an amount effective to prevent, treat or alleviate symptoms of a disease, disorder or condition involving activation of TRPV3, or for which reduced TRPV3 acitivity can reduce the severity, in a patient, but which does not cause QT interval elongation.

In another illustrative embodiment, the pharmaceutical preparation comprises an agent that inhibits heat-induced TRPV3-mediated current with an IC₅₀of 1 micromolar or less; and a pharmaceutically acceptable excipient or solvent, wherein the agent is provided in a dosage form providing an amount effective to prevent, treat or alleviate symptoms of a disease, disorder or condition involving activation of TRPV3, or for which reduced TRPV3 activity can reduce the severity, in a patient, but which does not cause QT interval elongation.

One preferred preparation is a topical formulation for reducing TRPV3 activity in skin or mucosa, comprising an agent that inhibits both 2-APB (2-aminoethyl diphenylborinate) and heat induced TRPV3-mediated current with an IC₅₀of 1 micromolar or less.

Another preferred preparation is a removable patch or bandage, comprising: (i) a polymeric base; and (ii) an agent that inhibits both 2-APB and heat induced TRPV3-mediated current with an IC₅₀of 1 micromolar or less.

Still another illustrative formultation is a skin exfoliant composition for topical application to an animal subject comprising a topical vehicle; one or more skin exfoliant ingredients selected from the group consisting of carboxylic acids, keto acids, α-hydroxy acids, β-hydroxy acids, retinoids, peroxides, and organic alcohols, said one or more skin exfoliant ingredients contained in a total amount of at least about 12% by weight and capable of inducing skin irritation and effecting exfoliation of the skin of said subject; and an agent that inhibits both 2-APB and heat induced TRPV3-mediated current with an IC₅₀of 1 micromolar or less, which agent is provided in an amount effective for analgesic, anti-irritant and/or anti-inflammatory effects when applied to skin.

Yet another embodiment is an antitussive composition for peroral administration comprising an agent that inhibits both 2-APB and heat induced TRPV3-mediated current with an IC₅₀of 1 micromolar or less, and an orally-acceptable pharmaceutical carrier in the form of an aqueous-based liquid, or solid dissolvable in the mouth, selected from the group consisting of syrup, elixer, suspension, spray, lozenge, chewable lozenge, powder, and chewable tablet. Such antitussive compositions can include one or more additional agents for treating cough, allergy or asthma symptom selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, expectorants, NK1, NK2 and NK3 tachykinin receptor antagonists, and GABA_Bagonists.

Still another embodiment is a metered dose aerosol dispenser containing an aerosol pharmaceutical composition for pulmonary or nasal delivery comprising an agent that inhibits both 2-APB and heat induced TRPV3-mediated current with an IC₅₀of 1 micromolar or less. For instance, it can be a metered dose inhaler, a dry powder inhaler or an air-jet nebulizer.

Still another embodiment is an eye ointment or eyedrops for ocular administration. Such ocular compositions may be useful for the treatment or alleviation of ocular pain including pain resulting from eye abrasion or post-surgical pain.

The present invention also relates to certain novel compounds, including purified preparations of those compounds. For instance, the invention provides compounds of Formula VII or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: X represents O, S, N(CN), CF₂, or C(CN)₂; Z represents O, S, N(CN), CF₂, or C(CN)₂; A represents N or C(R₂); G represents N or C(R₃); R₁represents H or a substituent; R₂′ represents a substituent; R₂represents, independently for each occurrence, H or a substituent; R₃represents, independently for each occurrence, H or a substituent; and D represents O or N. In certain preferred embodiments: X represents S and D represents O; and/or R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂′, R₂and R₃, independently for each occurrence, are selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano.

In certain embodiments, the compound can be represented by Formula VIIa:

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wherein: R₁represents H or a substituent; R₂and R₃are absent or represent one or more substituents on the ring to which they are attached; and R₂′ represents a substituent. In certain preferred embodiments, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano; and R₂′ is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano. In more preferred embodiments, each R₁is independently selected from H, lower alkyl, or alkoxy, or R₁taken together with the carbon to which it is attached forms a carbonyl. In certain embodiments, each R₂is absent or is independently selected from lower alkyl, alkoxy, or halogen; R₂′ is selected from lower alkyl, alkoxy, or halogen; and each R₃is absent or is independently selected from lower alkyl, alkoxy, CF₃, nitro, or halogen.

In certain preferred embodiments, R₁and R₂are absent; R₂′ represents CH₃; and R₃represents one or more substituents positioned meta or para to the nitrogen of the ring system.

In certain embodiments, the compound can be represented by Formula VIIb:

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wherein: R₁represents H or a substituent; R₂and R₃are absent or represent one or more substituents on the ring to which they are attached; and R₂′ represents a substituent.

For instance, R₁can be selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano; and R₂′ is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

In certain preferred embodiments, R₁is independently selected from H, lower alkyl, or alkoxy, or R₁taken together with the carbon to which it is attached forms a carbonyl.

In certain preferred embodiments, R₂is absent or each R₂is independently selected from lower alkyl, alkoxy, or halogen.

In certain preferred embodiments, R₂′ is selected from lower alkyl, alkoxy, or halogen.

In certain preferred embodiments, R₃is absent or each R₃is independently selected from lower alkyl, alkoxy, CF₃, nitro, or halogen.

In certain preferred embodiments, R₁, R₂, and R₃are absent.

In certain embodiments, the TRPV3 antagonist can be represented by Formula VIII or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: X represents O, S, N(CN), CF₂, or C(CN)₂; G represents N or C(R₃); R₁and R₂, 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; n represents 1, 2, or 3; R₃represents, independently for each occurrence, H or a substituent; R₅represents CH₂, O, NR₆; R₆represents H or lower alkyl; and D represents O or N.

In certain embodiments, Ar′ represents phenyl, thiophene, imidazole, thiazole, furan, oxazole, tetrazole, thiadiazole, pyridine, pyrimadine, or triazole.

In certain embodiments, X represents S and D represents O.

In certain embodiments, R₁is absent or, independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃, independently for each occurrence, are selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano.

In certain embodiments, the TRPV3 antagonist can be represented by Formula VIIIa:

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wherein: R₁, R₂and R₃are absent or represent one or more substituents on the ring to which they are attached.

In certain embodiments, R₁is absent or, independently for each occurrence, is selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano.

In certain embodiments, the TRPV3 antagonist is a compound of Formula IX or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

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wherein: A represents N or C(R₂); G represents N or C(R₃); R₁represents H or a substituent; R₂represents, independently for each occurrence, H or a substituent; R₃represents, independently for each occurrence, H or a substituent; R₃′ represents H, halogen, alkoxy, lower alkyl, perfluoroalkyl, aryl, heteroaryl, or CHR_3a; R₃″ represents H, halogen, lower alkyl, aryl, heteroaryl, or CHR_3a; R_3arepresents amino, heterocyclyl, carboxyl, ester, aryl, or heteroaryl; and D represents O or N, provided that when R₃′ is H, R₃″ is not H or lower alkyl, and when R₃′ is halogen, R₃″ is not H.

In certain embodiments, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃, independently for each occurrence, are selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

In certain embodiments, the TRPV3 antagonist is a compound can be represented by formula IXa

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wherein R₁represents H or a substituent; R₂is absent or represents a substituent; R₃is absent or represents a substituent; R₃′ represents H, halogen, alkoxy, lower alkyl, perfluoroalkyl, aryl, heteroaryl, or CHR_3a; R₃″ represents H, halogen, lower alkyl, aryl, heteroaryl, or CHR_3a; R_3arepresents amino, heterocyclyl, carboxyl, ester, aryl, or heteroaryl; and D represents O or N, provided that when R₃′ is H, R₃″ is not H or lower alkyl, and when R₃′ is halogen, R₃″ is not H.

In certain embodiments, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

In certain embodiments, the TRPV3 antagonist is a compound of Formula X or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

In certain embodiments, X represents S and D represents O.

In certain embodiments, the TRPV3 antagonist is a compound can be represented by Formula Xa:

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wherein: R₁represents H or a substituent; and R₂and R₃are absent or represent one or more substituents on the ring to which they are attached.

In certain embodiments, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano.

In certain embodiments, R₁is H; and R₂and R₃are absent.

In certain embodiments, the TRPV3 antagonist is a compound represented by Formula Xb:

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wherein: R₁represents H or a substituent; and R₂and R₃are absent or represent one or more substituents on the ring to which they are attached.

In certain embodiments, wherein R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano.

In certain embodiments, the TRPV3 antagonist is a compound of Formula XI or a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

In certain embodiments, X represents S and D represents O.

In certain embodiments, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; and R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano; and R_3bis selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

In certain embodiments, the TRPV3 antagonist is a compound represented by Formula XIa:

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wherein: R₁represents H or a substituent; R₂and R₃are absent or represent one or more substituents on the ring to which they are attached; and R_3brepresents a substituent.

In certain embodiments, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano; and R_3bis selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

In certain embodiments, R₁is H; R₂and R₃are absent; and R_3bis a halogen.

In certain embodiments, the TRPV3 antagonist is a compound can be represented by Formula XIb:

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wherein: R₁represents H or a substituent; R₂and R₃are absent or represent one or more substituents on the ring to which they are attached; and R_3brepresents a substituent.

In certain embodiments, R₁is selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl; R₂and R₃are absent or, independently for each occurrence, are selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, CF₃, or cyano; and R_3bis selected from lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a schematic representation of experiments performed using a thermal injury model.

FIG. 2 summarizes experiments showing the effectiveness of a TRPV3 inhibitor in diminishing pain in the thermal injury model. The reduction in pain is dose dependent.

FIG. 3 shows that the efficacy of a TRPV3 inhibitor in diminishing pain in the thermal injury model is specific, and that a TRPV3 inhibitor diminishes pain without affecting the uninjured paw. This suggests that TRPV3 inhibitors are specific for the facilitated state and are non-narcotic.

FIG. 4 shows that, in contrast to a TRPV3 inhibitor, morphine reduces pain but has a narcotic effect. Note the thermal escape latency after treatment with morphine is elevated above the baseline.

FIG. 5 provides a schematic representation of experiments performed using an automated formalin model.

FIG. 6 summarizes experiments showing the effectiveness of a TRPV3 inhibitor in diminishing pain in the formalin model. The TRPV3 inhibitor reduces pain during the second phase (also known as the Late Phase or the facilitated phase) following formalin injection. There is also a trend towards a reduction in the first phase (also known as the Early Phase).

FIG. 7 provides a schematic representation of experiments performed using the carrageenan model of acute inflammatory pain.

FIG. 8 summarizes experiments showing that a TRPV3 inhibitor reduces thermal hyperalgesia in the carrageenan model of acute inflammatory pain. The effectiveness of the TRPV3 inhibitor is similar to that of a TRPV1 inhibitor.

FIG. 9 provides a schematic representation of experiments performed using the Complete Freund's Adjuvant (CFA) model of inflammatory pain.

FIG. 10 summarizes experiments showing that a TRPV3 inhibitor reduces inflammatory pain in the CFA model. The effectiveness of the TRPV3 inhibitor is comparable or superior to that of diclofenac (a non-steroidal anti-inflammatory), as well as a TRPV1 inhibitor.

FIG. 11 summarizes experiments showing the responses for individual rats. TRPV3 inhibitor restores pain sensitivity to baseline after injection of CFA.

FIG. 12 summarizes experiments performed using a second TRPV3 inhibitor. This second TRPV3 inhibitor also reduces pain in the CFA model. Furthermore, the effectiveness of the TRPV3 inhibitor in reducing pain in the CFA model is similar to that of the non-steroidal anti-inflammatory, diclofenac.

FIG. 13
a-13b summarizes experiments measuring plasma levels of a potent TRPV3 inhibitor described in the example below. The TRPV3 inhibitor was administered intravenously (a) or orally in a suspension (b).

FIG. 14 shows the SAR for various compounds of Formula I versus TRPV3.

FIG. 15 shows the SAR for various compounds of Formula IV versus TRPV3 and in some instances versus other channels.

FIG. 16 shows the SAR for various compounds of Formula III versus TRPV3 and in some instances versus other channels.

FIG. 17 shows the SAR for various compounds of Formula II versus TRPV3 and in some instances versus other channels.

FIG. 18 shows the SAR for various compounds versus TRPV3.

DETAILED DESCRIPTION OF THE INVENTION

Cellular homeostasis is a result of the summation of regulatory systems involved in, amongst other things, the regulation of ion flux and membrane potential. Cellular homeostasis is achieved, at least in part, by movement of ions into and out of cells across the plasma membrane and within cells by movement of ions across membranes of intracellular organelles including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria and endocytic organelles including endosomes and lysosomes.

Movement of ions across cellular membranes is carried out by specialized proteins. TRP channels are one large family of non-selective cation channels that function to help regulate ion flux and membrane potential. TRP channels are subdivided into 6 sub-families including the TRPV (vanilloid receptor) family. TRPV3 is a member of the TRPV class of TRP channels.

Non-selective cation channels such as TRPV3 modulate the flux of calcium and sodium ions across cellular membranes. Sodium and calcium influx leads to a depolarization of the cell. This increases the probability that voltage-gated ion channels will reach the threshold required for activation. As a result, activation of non-selective cation channels can increase electrical excitability and increase the frequency of voltage-dependent events. Voltage dependent events include, but are not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contraction, cardiac muscle contraction, and skeletal muscle contraction.

TRPV3 is also highly expressed in skin. In a keratinocyte cell line, stimulation of TRPV3 leads to release of inflammatory mediators including interleukin-1. Thus TRPV3 may also play an important role in regulating inflammation and pain that results from the release of inflammatory stimuli (Xu et al., 2006)

TRPV3 proteins are thermosensitive channels expressed in skin cells (see, e.g., Peier et al. (2002) Science 296:2046-2049) and dorsal root ganglion, trigeminal ganglion, spinal cord and brain (see, e.g., Xu et al. (2002) Nature 418:181-185; Smith et al. (2002) Nature 418:186-188). Particular TRPV3 proteins that may be used in screening assays, as described herein, to identify compounds that modulate a function of TRPV3 include, but are not limited to human TRPV3, mouse TRPV3, and Drosophila TRPV3. U.S. Patent Application Publication 2004/0009537 (the “'537 publication”) disclosed sequences corresponding to human, mouse, and Drosophila TRPV3. For example, SEQ ID NOs 106 and 107 of the '537 publication correspond to the human nucleic acid and amino acid sequences, respectively. SEQ ID Nos 108 and 109 of the '537 publication correspond to the mouse nucleic acid and amino acid sequences, respectively. The Drosophila protein is approximately 25% identical and 41% homologous to the human protein over approximately 49% of the length of the protein, and approximately 26% identical and 42% homologous to the mouse protein over approximately 49% of the length of the protein.

Other exemplary human TRPV3 nucleic acid and amino acid sequences are disclosed in GenBank at the following accession numbers: gi:21912412 (accession no. AJ487035); gi:21435923 (accession no. AF514998); gi:22651775 (accession no. AY118268); gi:85397600 (accession no. BC104868); and gi:22651773 (accession no. AY118267). The TRPV3 sequences and disclosures provided at these accession numbers are hereby incorporated by reference in their entirety. Compounds that inhibit one or more functions or activities of TRPV3, according to the present invention, inhibit one or more functions of any of the TRPV3 proteins provided herein. Furthermore, compounds that inhibit one or more functions or activities of TRPV3, according to the present invention, inhibit one or more functions of a TRPV3 protein encoded by a nucleic acid sequence that hybridizes under stringent conditions, including a wash step of 0.2×SSC at 65° C., to a TRPV3 nucleic acid sequence provided herein.

TRPV3 is expressed in a pattern consistent with a role in, among other things, pain. TRPV3 is expressed in tissues containing pain-sensing neurons (nociceptors). Nociceptors mediate responsiveness to force, heat, cold, chemicals, and inflammation. In addition, skin which expresses high levels of TRPV3 plays a significant role in pain. Additional evidence implicating TRPV3 in, among other processes, pain includes the TRPV3 knock-out mouse which displays abnormal responses to painful stimuli. Further evidence indicates that TRPV3 expression increases in the skin cells of breast cancer patients who report significant pain (Gopinath et al., 2005).

Accordingly, modulating the function of TRPV3 proteins provides a means of modulating calcium homeostasis, sodium homeostasis, membrane polarization, and/or intracellular calcium levels, and compounds that can modulate TRPV3 function are useful in many aspects, including, but not limited to, maintaining calcium homeostasis, modulating intracellular calcium levels, modulating membrane polarization, and treating or preventing diseases, disorders, or conditions associated with calcium and/or sodium homeostasis or dyshomeostasis. In one embodiment, compounds that modulate TRPV3 function can be used in the treatment of diseases, injuries, disorders, or conditions caused or exacerbated, in whole or in part, by regulation or misregulation of TRPV3 activity. In one embodiment, compounds that inhibit a TRPV3 function can be used in the treatment of diseases, injuries, disorders, or conditions caused or exacerbated, in whole or in part, by regulation or misregulation of TRPV3 activity. In still another embodiment, compounds that inhibit a TRPV3 function can be used in the treatment of pain.

In certain embodiments, R is H, W is O or S, and X is O or S.

In certain embodiments, X is CH₂.

In certain preferred embodiments, the TRPV3 antagonist is represented in Formula Ia, or is a salt, solvate, hydrate, oxidative metabolite or prodrug thereof:

Exemplary compounds of Formula I and Ia include:

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Other exemplary compounds of Formula I are shown in FIG. 14. FIG. 14 shows the SAR for various compounds of Formula I versus TRPV3.

In certain embodiments of Formulas I and Ia, Y is N(U)(Arl), and in such embodiments, Y can represent, for example,

- Ar′ represents phenyl, thiophene, imidazole, thiazole, furan, oxazole, tetrazole, thiadiazole, pyridine, pyrimadine, or triazole;
- each R₁is independently selected from H, lower alkyl, alkoxy, carboxyl, ester, amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, or R₁taken together with the carbon to which it is attached forms a carbonyl or thiocarbonyl;
- each R₂is independently selected from H, lower alkyl, alkoxy, carboxyl, ester amido, sulfonamido, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, halogen, CF₃, or cyano;