Agonists of hedgehog signaling pathways and uses related thereto
First Claim
Patent Images
1. A method for agonizing the hedgehog pathway in a cell, comprising contacting the cell with a hedgehog agonist represented in general formula (II):
-
whereinAr and Ar′
independently represent substituted or unsubstituted aryl or heteroaryl rings;
Y, independently for each occurrence, is absent or represents —
N(R)—
, —
O—
, —
S—
, or —
Se—
;
X is selected from —
C(═
O)—
, —
C(═
S)—
, —
S(O2)—
, —
S(O)—
, —
C(═
NCN)—
, —
P(═
O)(OR)—
, and a methylene group optionally substituted with 1-2 groups selected from lower alkyl, alkenyl, and alkynyl groups;
M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two adjacent M taken together represent substituted or unsubstituted ethene or ethyne, wherein some or all occurrences of M in Mj form all or part of a cyclic ring;
R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, alkynyl, alkenyl, or alkyl, or two R taken together may form a 4- to 8-membered ring;
Cy′
represents substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl;
j represents, independently for each occurrence, an integer from 0 to 10; and
i represents, independently for each occurrence, an integer from 0 to 5.
4 Assignments
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Accused Products
Abstract
The present invention makes available methods and reagents for inducing activation of a hedgehog pathway in a cell or tissue comprising contacting the cell with a hedgehog agonist, such as a small molecule, in a sufficient amount to achieve a therapeutic result. In certain embodiments, the methods and reagents may be employed to correct or inhibit an aberrant or unwanted growth state, e.g., by antagonizing a normal ptc pathway or agonizing smoothened or hedgehog activity.
-
Citations
75 Claims
-
1. A method for agonizing the hedgehog pathway in a cell, comprising contacting the cell with a hedgehog agonist represented in general formula (II):
-
wherein Ar and Ar′
independently represent substituted or unsubstituted aryl or heteroaryl rings;
Y, independently for each occurrence, is absent or represents —
N(R)—
, —
O—
, —
S—
, or —
Se—
;
X is selected from —
C(═
O)—
, —
C(═
S)—
, —
S(O2)—
, —
S(O)—
, —
C(═
NCN)—
, —
P(═
O)(OR)—
, and a methylene group optionally substituted with 1-2 groups selected from lower alkyl, alkenyl, and alkynyl groups;
M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two adjacent M taken together represent substituted or unsubstituted ethene or ethyne, wherein some or all occurrences of M in Mj form all or part of a cyclic ring;
R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, alkynyl, alkenyl, or alkyl, or two R taken together may form a 4- to 8-membered ring;
Cy′
represents substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl;
j represents, independently for each occurrence, an integer from 0 to 10; and
i represents, independently for each occurrence, an integer from 0 to 5. - View Dependent Claims (2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75)
p, independently for each occurrence, represents an integer from 0 to 10.
-
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29. The method of claim 1, wherein Y is absent and 4 occurrences of M in Mj form part of a ring.
-
30. The method of claim 29, wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.
-
31. The method of claim 29, wherein X is selected from —
- C(═
O)—
, —
C(═
S)—
, and —
S(O2)—
.
- C(═
-
32. The method of claim 29, wherein NR2 represents a primary amine or a secondary or tertiary amine substituted with one or two lower alkyl groups.
-
33. The method of claim 29, wherein Cy′
- is a substituted or unsubstituted aryl or heteroaryl.
-
34. The method of claim 33, wherein Cy′
- is bicyclic.
-
35. The method of claim 34, wherein Cy′
- represents a substituted or unsubstituted benzothiophene.
-
36. The method of claim 35, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.
-
37. The method of claim 36, wherein the ring is a cyclohexyl ring.
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38. The method of claim 36, wherein each R independently represents H or a lower alkyl.
-
39. The method of claim 38, wherein NR2 represents a secondary amine.
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40. The method of claim 37, wherein each R independently represents H or a lower alkyl.
-
41. The method of claim 40, wherein NR2 represents a secondary amine.
-
42. The method of claim 38, wherein
i is zero except for Mi between Ar and N; - and
all Y are absent.
- and
-
43. The method of claim 40, wherein
i is zero except for Mi between Ar and N; - and
all Y are absent.
- and
-
44. The method of claim 29, wherein the ring is a cyclohexyl ring.
-
45. The method of claim 44, wherein Cy′
- represents a substituted or unsubstituted benzothiophene.
-
46. The method of claim 45, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.
-
47. The method of claim 44, wherein each R independently represents H or a lower alkyl.
-
48. The method of claim 47, wherein NR2 represents a secondary amine.
-
49. The method of claim 46, wherein each R independently represents H or a lower alkyl.
-
50. The method of claim 49, wherein NR2 represents a secondary amine.
-
51. The method of claim 47, wherein
i is zero except for Mi between Ar and N; - and
all Y are absent.
- and
-
52. The method of claim 49, wherein
i is zero except for Mi between Ar and N; -
4 occurrences of M in Mj form part of a ring; and
all Y are absent.
-
-
53. The method of claim 32, wherein each R independently represents H or a lower alkyl.
-
54. The method of claim 53, wherein NR2 represents a secondary amine.
-
55. The method of claim 53, wherein Cy′
- represents a substituted or unsubstituted benzothiophene.
-
56. The method of claim 55, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.
-
57. The method of claim 52, wherein the ring is a cyclohexyl ring.
-
58. The method of claim 56, wherein
i is zero except for Mi between Ar and N; and all Y are absent.
-
59. The method of claim 57, wherein
i is zero except for Mi between Ar and N; - and
all Y are absent.
- and
-
60. The method of claim 29, wherein
4 occurrences of M in Mj form part of a ring; -
X is selected from —
C(═
O)—
or —
C(═
S)—
; and
Cy′
is a substituted or unsubstituted aryl or heteroaryl ring.
-
-
61. The method of claim 60, wherein Cy′
- is heteroaryl.
-
62. The method of claim 60, wherein Cy′
- is bicyclic.
-
63. The method of claim 60, wherein the ring is a cycloalkyl ring.
-
64. The method of claim 63, wherein the ring is a cyclohexyl ring.
-
65. The method of claim 64, wherein Cy′
- represents a substituted or unsubstituted benzothiophene.
-
66. The method of claim 65, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.
-
67. The method of claim 64, wherein each R independently represents H or a lower alkyl group.
-
68. The method of claim 65, wherein NR2 represents a secondary amine.
-
69. The method of claim 66, wherein each R independently represents H or a lower alkyl group.
-
70. The method of claim 62, wherein Cy′
- represents a substituted or unsubstituted benzothiophene.
-
71. The method of claim 70, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.
-
72. The method of claim 71, wherein the ring is a cyclohexyl ring.
-
73. The method of claim 71, wherein each R independently represents H or a lower alkyl group.
-
74. The method of claim 72, wherein each R independently represents H or a lower alkyl group.
-
75. The method of claim 12, wherein the therapeutic or cosmetic application is promoting hair growth.
-
7. The method of claim wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED50 of 1 mM or less.
Specification