1. An article of manufacture comprising a computer readable storage medium having code executed to perform operations, the operations comprising:
providing a module mapping associating a plurality of first type query translator modules with a first data store type to which the first query translator modules apply and associating a plurality of second query translator modules with a second data store type to which the second query translator modules apply, wherein the first and second query translator modules for the first and second data store types include database specific operations to implement query optimization for the first and second data store types to which the first and second query translator modules respectively apply and include first and second resolve modules, respectively;
receiving a query to query a target data store;
determining whether the target data store is of the first data store type or the second data store type;
determining from the module mapping the first query translators to use in response to determining that the target data store is of the first data store type and the second query translator modules to use in response to determining that the target data store is of the second data store type;
generating a parse tree of nodes;
grouping the nodes according to query parts to produce a query graph;
forwarding the query graph to the first or second resolve module from the determined first or second query translator modules to validate that the query attributes are valid attributes in the target data store; and
in response to validating the query parts, performing:
using the first query translator modules to translate the received query to a query execution plan in response to determining that the target data store is of the first data store type; and
using the second query translator modules to translate the received query to a query execution plan in response to determining that the target data store is of the second data store type.
2. The article of manufacture of claim 1, wherein the first and second resolve modules perform different resolve validation operations specific to their data store type.
3. The article of manufacture of claim 1, wherein the first and second query translator modules include first and second type check modules, wherein the type check modules validate query operations for queried attributes, wherein the first and second type check modules perform different validation operations specific to their data store type.
4. The article of manufacture of claim 1, wherein the first data store comprises an application specific data store and the second data store comprises an object oriented or relational database.
5. The article of manufacture of claim 4, wherein the first query translator generates an access plan to the application specific data store using application specific program statements and wherein the second query translator module generates structured query language statements to implement the received query against the object oriented or relational database data store.
6. A system in communication with at least one data store;
comprising:
a memory including:
a plurality of first type query translator modules including information indicating a first data store type to which the first query translator modules apply;
a plurality of second query translator modules including information indicating a second data store type to which the first query translator modules apply, wherein the first and second query translator modules for the first and second data store types include database specific operations to implement query optimization for the first and second data store types to which the first and second query translator modules respectively apply and include first and second resolve modules, respectively; and
a query engine executed to perform operations, the operations comprising:
receiving a query to query a target data store comprising one of the at least one data store;
determining whether the target data store is of the first data store type or the second data store type;
generating a parse tree of nodes;
grouping the nodes according to query parts to produce a query graph;
forwarding the query graph to the first or second resolve module from the determined first or second query translator modules to validate that the query attributes are valid attributes in the target data store; and
in response to validating the query parts, performing:
using the first query translator modules to translate the received query to a query execution plan in response to determining that the target data store is of the first data store type; and
using the second query translator modules to translate the received query to a query execution plan in response to determining that the target data store is of the second data store type.
7. The system of claim 6, wherein the first and second query translator modules include first and second resolve modules, wherein the first and second resolve modules perform different resolve validation operations specific to their data store type.
8. The system of claim 6, wherein the first and second query translator modules include first and second type check modules, wherein the type check modules validate query operations for queried attributes, wherein the first and second type check modules perform different validation operations specific to their data store type.
9. The system of claim 6, wherein the first data store comprises an application specific data store and the second data store comprises an object oriented or relational database.
10. A method, comprising:
providing a plurality of first type query translator modules including information indicating a first data store type to which the first query translator modules apply;
providing a plurality of second query translator modules including information indicating a second data store type to which the first query translator modules apply;
receiving a query to query a target data store, wherein the first and second query translator modules for the first and second data store types include database specific operations to implement query optimization for the first and second data store types to which the first and second query translator modules respectively apply and include first and second resolve modules, respectively;
determining whether the target data store is of the first data store type or the second data store type;
generating a parse tree of nodes;
grouping the nodes according to query parts to produce a query graph;
forwarding the query graph to the first or second resolve module from the determined first or second query translator modules to validate that the query attributes are valid attributes in the target data store; and
in response to validating the query parts, performing:
using the first query translator modules to translate the received query to a query execution plan in response to determining that the target data store is of the first data store type; and
using the second query translator modules to translate the received query to a query execution plan in response to determining that the target data store is of the second data store type.
11. The method of claim 10, wherein the first and second resolve modules perform different resolve validation operations specific to their data store type.
12. The method of claim 10, wherein the first and second query translator modules include first and second type check modules, wherein the type check modules validate query operations for queried attributes, wherein the first and second type check modules perform different validation operations specific to their data store type.
13. The method of claim 10, wherein the first data store comprises an application specific data store and the second data store comprises an object oriented or relational database.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. (canceled)
2. 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\u2032 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.
3-36. (canceled)
37. A pharmaceutical preparation suitable for use in a human patient for treating or preventing a condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity, comprising 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, and one or more pharmaceutically acceptable excipients:
wherein
Ar and Ar\u2032 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 1-3 atoms; and
wherein said compound inhibits TRPV3 with an IC50 of 10 micromolar or less.
38. 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\u2032 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.
39. The compound of claim 38, wherein Ph represents a 2,3-disubstituted phenyl ring, wherein each substituent is independently selected from substituted or unsubstituted alkyl.
40. The compound of claim 38, wherein Ph represents a 2,4-disubstituted phenyl ring, wherein each substituent is independently selected from substituted or unsubstituted alkyl.
41. The compound of claim 38, wherein Ph represents a 2,5-disubstituted phenyl ring, wherein each substituent is independently selected from substituted or unsubstituted alkyl.
42. The compound of claim 38, wherein Ph represents a 2,6-disubstituted phenyl ring, wherein each substituent is independently selected from substituted or unsubstituted alkyl, alkoxy, or hydroxy.
43. The compound of claim 38, wherein Ph represents a monosubstituted 2-substituted phenyl ring, wherein said substituent is a trifluoromethyl group.
44. The compound of claim 38, wherein Ph represents a 3,4-disubstituted phenyl ring, wherein each substituent is independently selected from trifluoromethyl, methyl, or halogen.
45. The compound of claim 38, wherein Ph represents a monosubstituted 3-substituted phenyl ring, wherein said substituent is selected from ethyl or a trifluoromethyl group.
46. 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\u2032 represents lower alkyl; and
Ph represents a substituted or unsubstituted phenyl ring.
47. 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\u2032 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.
48. The method of claim 47, wherein said compound inhibits a TRPV3 mediated current with an IC50 of 1 micromolar or less.
49. The method of claim 47, wherein said compound inhibits a TRPV3 mediated current with an IC50 of 100 nanomolar or less.
50. 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\u2032 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.
51. The method of claim 50, wherein Ar\u2032 represents a substituted or unsubstituted phenyl ring.
52. The method of claim 50, wherein Ar\u2032 is optionally substituted with one or more of the following: 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, \u2014NHSO2NH2, \u2014OCH2CH2NR7, or two adjacent substituents together represent \u2014NHSO2NH\u2014 or \u2014NHC(O)NH\u2014 forming a heterocycle with the carbons to which they are attached, or azido; and R7 is lower alkyl.
53. The method of claim 51, wherein Ar\u2032 represents
wherein
R5 is selected from hydrogen, substituted or unsubstituted alkyl, nitro, amino, \u2014NHSO2NH2, \u2014OCH2CH2NR7, or \u2014OR, wherein R represents hydrogen, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
R8 is selected from hydrogen, halogen, lower alkyl, lower alkoxy, amino, or \u2014NHSO2NH2, or R5 and R8 together represent \u2014NHSO2NH\u2014 or \u2014NHC(O)NH\u2014 forming a heterocycle with the carbons to which they are attached;
R7 represents lower alkyl; and
R6 represents hydrogen, halogen, lower alkyl, lower alkoxy, amino, or \u2014NHSO2NH2.
54. The method of claim 53, wherein R5 is \u2014OR, wherein R represents hydrogen, a pharmaceutically acceptable counterion, or a physiologically labile moiety; R8 is lower alkoxy; and R6 is hydrogen.
55. The method of claim 50, wherein Ar represents a substituted or unsubstituted phenyl ring.
56. The method of claim 50, wherein Ar is optionally substituted with one or more of the following: 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, azido, \u2014NHSO2NH2, or \u2014NHSO2CH3.
57. The method of claim 55, wherein Ar represents
wherein
R1 and R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl, hydroxyl, lower alkoxy, cyano, nitro, amino, halogen, thioether, or lower cycloalkyl;
R3 is selected from hydrogen, substituted or unsubstituted alkyl, lower alkoxy, cyano, amino, \u2014NHSO2NH2, or \u2014NHSO2CH3; and
R4 is selected from hydrogen, substituted or unsubstituted alkyl, hydroxyl, lower alkoxy, \u2014NHSO2NH2, or \u2014NHSO2CH3.
58. The method of claim 57, wherein R1 and R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or lower alkoxy; R3 is selected from hydrogen or substituted or unsubstituted alkyl; and R4 is selected from hydrogen or substituted or unsubstituted alkyl.
59. The method of claim 50, wherein G1 and G2 are lower alkyl.
60. The method of claim 50, wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane.
61. The method of claim 50, wherein the compound is represented by Formula II:
wherein
Q is an aryl or heteroaryl group;
R is absent or represents one or more substituents;
Ar and Ar\u2032 each independently represent an aryl or heteroaryl group; and
L represents a linker having 1-3 atoms.
62. The method of claim 61, wherein each R is independently selected from lower alkyl, lower alkoxy, carboxyl, ester, ketone, amido, sulfonamide, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, trifluoromethyl, cyano, acyloxy, or \u2014NHSO2NH2.
63. The method of claim 61, wherein R is absent.
64. The method of claim 61, wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane.
65. The method of claim 61, wherein the compound is represented by Formula III:
wherein
R is absent or represents one or more substituents;
Ar and Ar\u2032 each independently represent an aryl or heteroaryl group; and
L represents a linker having 1-3 atoms.
66. The method of claim 65, wherein each R is independently selected from lower alkyl, lower alkoxy, carboxyl, ester, ketone, amido, sulfonamide, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, trifluoromethyl, cyano, acyloxy, or \u2014NHSO2NH2.
67. The method of claim 65, wherein R is absent.
68. The method of claim 65, wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane.
69. The method of claim 68, wherein L is cyclopropane.
70. The method of claim 50, wherein said compound inhibits TRPV3-mediated current.
71. The method of claim 70, wherein said compound inhibits TRPV3 with an IC50 at least one order of magnitude lower than its IC50 for inhibition of at least one of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and HERG.
72. (canceled)
73. The method of claim 70, wherein said compound inhibits TRPV3 with an IC50 at least one order of magnitude lower than its IC50 for inhibition of TRPV1.
74. (canceled)
75. The method of claim 70, wherein said compound inhibits TRPV3 with an IC50 at least one order of magnitude more potent that its Ki for the AMPA receptor.
76. The method of claim 70, wherein said compound inhibits TRPV3 with an IC50 of 1 \u03bcM or less.
77. The method of claim 70, wherein said compound inhibits TRPV3 with an IC50 of 100 nM or less.
78. The method of claim 70, used to prevent, treat or alleviate symptoms of a disorder or condition selected from the group consisting of acute or chronic pain, touch sensitivity, burns, inflammation, diabetic neuropathy, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), migraine, incontinence, fever, hot flashes, osteoarthritis, rheumatoid arthritis and cough, or is used as a depilatory to promote loss of or inhibit the growth of hair on a patient.
79. The method of claim 70, wherein the compound is administered conjointly with one or 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.
80. The method of claim 70, wherein the compound has an IC50 for TRPV3 inhibition, and when administered at that concentration, the compound does not cause QT interval elongation in the patient.
81. 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\u2032 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
82. The method of claim 81, wherein Ar\u2032 represents a substituted or unsubstituted phenyl ring.
83. The method of claim 81, wherein Ar\u2032 is optionally substituted with one or more of the following: 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, \u2014NHSO2NH2, \u2014OCH2CH2NR7, or two adjacent substituents together represent \u2014NHSO2NH\u2014 or NHC(O)NH\u2014 forming a heterocycle with the carbons to which they are attached, or azido; and R7 is lower alkyl.
84. The method of claim 82, wherein Ar\u2032 represents
wherein
R5 is selected from hydrogen, substituted or unsubstituted alkyl, nitro, amino, \u2014NHSO2NH2, \u2014OCH2CH2NR7, or \u2014OR, wherein R represents hydrogen, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
R8 is selected from hydrogen, halogen, lower alkyl, lower alkoxy, amino, or \u2014NHSO2NH2, or R5 and R8 together represent \u2014NHSO2NH\u2014 or \u2014NHC(O)NH\u2014 forming a heterocycle with the carbons to which they are attached;
R7 represents lower alkyl; and
R6 represents hydrogen, halogen, lower alkyl, lower alkoxy, amino, or \u2014NHSO2NH2.
85. The method of claim 84, wherein R5 is \u2014OR, wherein R represents hydrogen, a pharmaceutically acceptable counterion, or a physiologically labile moiety; R8 is lower alkoxy; and R6 is hydrogen.
86. The method of claim 81, wherein Ar represents a substituted or unsubstituted phenyl ring.
87. The method of claim 81, wherein Ar is optionally substituted with one or more of the following: 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, azido, \u2014NHSO2NH2, or \u2014NHSO2CH3.
88. The method of claim 86, wherein Ar represents
wherein
R1 and R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl, hydroxyl, lower alkoxy, cyano, nitro, amino, halogen, thioether, or lower cycloalkyl;
R3 is selected from hydrogen, substituted or unsubstituted alkyl, lower alkoxy, cyano, amino, \u2014NHSO2NH2, or \u2014NHSO2CH3; and
R4 is selected from hydrogen, substituted or unsubstituted alkyl, hydroxyl, lower alkoxy, \u2014NHSO2NH2, or \u2014NHSO2CH3.
89. The method of claim 88, wherein R1 and R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or lower alkoxy; R3 is selected from hydrogen or substituted or unsubstituted alkyl; and R4 is selected from hydrogen or substituted or unsubstituted alkyl.
90. The method of claim 81, wherein G1 and G2 are lower alkyl.
91. The method of claim 81, wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane.
92. The method of claim 81, wherein the compound is represented by Formula II:
wherein
Q is an aryl or heteroaryl group;
R is absent or represents one or more substituents;
Ar and Ar\u2032 each independently represent an aryl or heteroaryl group; and
L represents a linker having 1-3 atoms.
93. The method of claim 92, wherein each R is independently selected from lower alkyl, lower alkoxy, carboxyl, ester, ketone, amido, sulfonamide, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, trifluoromethyl, cyano, acyloxy, or \u2014NHSO2NH2.
94. The method of claim 92, wherein R is absent.
95. The method of claim 92, wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane.
96. The method of claim 92, wherein the compound is represented by Formula III:
wherein
R is absent or represents one or more substituents;
Ar and Ar\u2032 each independently represent an aryl or heteroaryl group; and
L represents a linker having 1-3 atoms.
97. The method of claim 96, wherein each R is independently selected from lower alkyl, lower alkoxy, carboxyl, ester, ketone, amido, sulfonamide, heterocyclyl, cycloalkyl, hydroxyl, amino, acylamino, thioether, sulfonylamino, nitro, halogen, trifluoromethyl, cyano, acyloxy, or \u2014NHSO2NH2.
98. The method of claim 96, wherein R is absent.
99. The method of claim 96, wherein L represents a linker selected from ethylene, substituted or unsubstituted, cis- or trans-ethene, or cyclopropane.
100. The method of claim 99, wherein L represents cyclopropane.
101. The method of claim 81, wherein said compound inhibits TRPV3-mediated current.
102. The method of claim 101, wherein said compound inhibits TRPV3 with an IC50 at least one order of magnitude lower than its ICso for inhibition of at least one of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and HERG.
103. (canceled)
104. The method of claim 101, wherein said compound inhibits TRPV3 with an IC50 at least one order of magnitude lower than its ICso for inhibition of TRPV1.
105. (canceled)
106. The method of claim 101, wherein said compound inhibits TRPV3 with an IC50 at least one order of magnitude more potent than its Ki for the AMPA receptor.
107. The method of claim 101, wherein said compound inhibits TRPV3 with an IC50 of 1 \u03bcM or less.
108. The method of claim 101, wherein said compound inhibits TRPV3 with an IC50 of 100 nM or less.
109. The method of claim 101, wherein the pain is oral pain.
110. The method of claim 101, wherein the pain is cancer-related pain.
111. The method of claim 101, wherein the compound is administered orally.
112. The method of claim 101, wherein the pain is a symptom of a disease selected from Fabray’s disease, fibromyalgia, pancreatitis, or complex regional pain syndrome.
113. The method of claim 101, wherein the pain is neuropathic pain, nociceptive pain, or inflammatory pain.