Claims
- 1. A compound of the formula
- 2. A compound of claim 1 where Y is phenyl, pyridyl, thienyl or furyl.
- 3. A compound of claim 1 where Y is phenyl.
- 4. A compound of claim 3 where the phenyl ring is 1, 4 (para) substituted.
- 5. A compound of claim 1 where Y is naphthyl.
- 6. A compound of claim 1 where Y is pyridyl.
- 7. A compound of claim 1 where Y is thienyl or furyl.
- 8. A compound of claim 1 where Z is —(CR1—CR1)n′—, and n′ is 3, 4, or 5 and Y represents a direct valence bond between said (CR1═CR1)n′ group and B.
- 9. A compound of claim 1 where R2 is H, F, or CF3.
- 10. A compound of claim 1 where R3 is H or methyl.
- 11. A compound of claim 1 where R14 is (R15)r- phenyl.
- 12. A compound of claim 1 where R14 is (R15)r-heteroaryl.
- 13. A compound of claim 12 where R14 is (R15)r-heteroaryl where the heteroaryl group is a 5 or six membered ring having 1 or 2 heteroatoms.
- 14. A compound of claim 13 where the heteroaryl group is selected from 2-pyridyl, 3-pyridyl, 2-thienyl and 2-thiazolyl.
- 15. A compound of claim 1 where the R15 group is H, CF3, F, lower alkyl, lower alkoxy, hydroxy or chlorine.
- 16. A compound of claim 1 where Z is —C≡C—.
- 17. A compound of claim 1 where Z is —N═N—.
- 18. A compound of claim 1 where Z is —CO—NR1—.
- 19. A compound of claim 1 where Z is —CS—NR1—.
- 20. A compound of claim 1 where Z is —CS—NR1—.
- 21. A compound of claim 1 where Z is —COO—.
- 22. A compound of claim 1 where Z is —(CR1═CR1)n′— and n′ is 1.
- 23. A compound of claim 1 where X is [C(R1)2]n and n is 1 or 0.
- 24. A compound of claim 1 where X is S, O, or NR′.
- 25. A method of treating a pathological condition in a mammal, said condition associated with a retinoic acid receptor activity, said method comprising administering to said mammal a retinoid antagonist or negative hormone capable of binding to a retinoic acid receptor subtype selected from the group consisting of RAEα, RARβ and RARγ, said antagonist or negative hormone being administered in an amount pharmaceutically effective to provide a therapeutic benefit against said pathological condition in said mammal.
- 26. The method of claim 25 wherein the pathological condition is the toxicity or undesired side effects resulting from administration of a retinoid compound to said mammal, and wherein said therapeutic benefit is the prevention or amelioration of said toxicity or undesired side effects.
- 27. The method of claim 25 wherein the retinoid antagonist or negative hormone is administered in order to cure or ameliorate a pre-existing pathological condition caused by intake of a retinoid drug or vitamin A or vitamin A precursors by the mammal.
- 28. The method of claim 25 wherein the retinoid antagonist or negative hormone is administered topically to block or ameliorate undesired topical side effects of a retinoid drug administered for a therapeutic purpose.
- 29. The method of claim 25 wherein the retinoid antagonist or negative hormone is administered topically to block or ameliorate undesired topical side effects of a retinoid drug administered systemically for a therapeutic purpose.
- 30. The method of claim 25 wherein the retinoid antagonist or negative hormone is administered topically to treat a pre-existing condition or side effect caused by a retinoid drug or vitamin A.
- 31. The method of claim 25 wherein the retinoid antagonist or negative hormone is administered systemically to treat a pre-existing condition or side effect caused by a retinoid drug or vitamin A.
- 32. The method of claim 25 wherein the retinoid antagonist or negative hormone is administered systemically to block or ameliorate bone toxicity caused by coadministration of a retinoid drug or vitamin A.
- 33. The method of claim 25, wherein the retinoid antagonist or negative hormone binds to said subtype of retinoid receptor with a Kd of less than approximately 1 micromolar.
- 34. The method of claim 25, wherein a retinoid antagonist is administered.
- 35. The method of claim 25, wherein the negative hormone or antagonist has the formula:
- 36. A method of claim 35 where in the formula of the antagonist or negative hormone Y is phenyl, pyridyl, thienyl or furyl.
- 37. A method of claim 35 where in the formula of the antagonist or negative hormone Y is phenyl.
- 38. A method of claim 37 where in the formula of the antagonist or negative hormone the phenyl ring is 1,4 (para) substituted.
- 39. A method of claim 35 where in the formula of the antagonist or negative hormone Y is naphthyl.
- 40. A method of claim 35 where in the formula of the antagonist or negative hormone Y is pyridyl.
- 41. A method of claim 35 where in the formula of the antagonist or negative hormone Y is thienyl or furyl.
- 42. A method of claim 35 where in the formula of the antagonist or negative hormone Z is —(CR1═CR1)n′—, and n′ is 3, 4 or 5 and Y represents a direct valence bond between said (CR1═CR1)n′ group and B.
- 43. A method of claim 35 where in the formula of the antagonist or negative hormone R2 is H, F, or CF3.
- 44. A method of claim 35 where in the formula of the antagonist or negative hormone R3 is H or methyl.
- 45. A method of claim 35 where in the formula of the antagonist or negative hormone R14 is (R15)r-phenyl.
- 46. A method of claim 35 where in the formula of the antagonist or negative hormone R14 is (R15)r-heteroaryl.
- 47. A method of claim 46 where in the formula of the antagonist or negative hormone R14 is (R15)r-heteroaryl where the heteroaryl group is a 5 or six membered ring having 1 or 2 heteroatoms.
- 48. A method of claim 47 where in the formula of the antagonist the heteroaryl group is selected from 2-pyridyl, 3-pyridyl, 2-thienyl and 2-thiazolyl.
- 49. A method of claim 35 where in the formula of the antagonist or negative hormone the R15, group is H, CF3, F, lower alkyl, lower alkoxy, hydroxy or chlorine.
- 50. A method of claim 35 where in the formula of the antagonist or negative hormone Z is —C≡C—.
- 51. A method of claim 35 where in the formula of the antagonist or negative hormone Z is —N═N—.
- 52. A method of claim 35 where in the formula of the antagonist or negative hormone of claim 1 where Z is —CO—NR1—.
- 53. A method of claim 35 where in the formula of the antagonist or negative hormone Z is —CS—NR1—.
- 54. A method of claim 53 where in the formula of the antagonist or negative hormone R1 is H.
- 55. A method of claim 35 where in the formula of the antagonist or negative hormone Z is —COO—.
- 56. A method of claim 35 where in the formula of the antagonist or negative hormone Z is —(CR1═CR1)n′— and n′ is 1.
- 57. A method of claim 35 where in the formula of the antagonist or negative hormone X is [C(R1)2]n and n is 1 or 0.
- 58. A method of claim 35 where in the formula of the antagonist or negative hormone X is S, O or NR′.
- 59. A compound of the formula
- 60. A compound of claim 59 where Y is phenyl, pyridyl, thienyl or furyl.
- 61. A compound of claim 59 where Y is phenyl.
- 62. A compound of claim 61 where the phenyl ring is 1,4 (para) substituted.
- 63. A compound of claim 59 where Y is pyridyl.
- 64. A compound of claim 59 where Y is thienyl or furyl.
- 65. A compound of claim 59 where R14 is (R15)r-phenyl.
- 66. A compound of claim 59 where R14 is (R15)r-heteroaryl.
- 67. A compound of claim 66 where R14 is (R15)r-heteroaryl where the heteroaryl group is a 5 or six membered ring having 1 or 2 heteroatoms.
- 68. A compound of claim 67 where the heteroaryl group is selected from 2-pyridyl, 3-pyridyl, 2-thienyl and 2-thiazolyl.
- 69. A compound of claim 59 where the R15 group is H, CF3, F, lower alkyl, lower alkoxy, hydroxy or chlorine.
- 70. A compound of claim 59 where X is [C(R1)2]n.
- 71. A compound of claim 70 where R1 is CH3 and n is 1.
- 72. A compound of claim 59 where X is S, O or NR′.
- 73. A compound of claim 59 where A is (CH2)q where q is 0-5 and where B is COOH or a pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
- 74. A compound of claim 59 where p is zero.
- 75. A compound of claim 59 where p is 1.
- 76. A compound of the formula
- 77. A compound of claim 76 wherein p is 1.
- 78. A compound of claim 76 where p is zero.
- 79. A compound of claim 78 where A is (CH2)q where q is 0-5, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.
- 80. A compound of claim 79 where R. is CH3.
- 81. A compound of claim 80 where R2, R3, R16 and R17 are hydrogen.
- 82. A compound of claim 81 where R15 is H or CH3, and when R15 is CH3 it occupies the 4 position of the phenyl ring.
- 83. A compound of claim 82 which is 4-[3-oxo-3-(7,8-dihydro-5-(4-methylphenyl)-8,8dimethyl-2-naphthalenyl)-1-propenyl]-benzoic acid or 4-[3-oxo-3-(7,8-dihydro-5-phenyl-8,8-dimethyl-2-naphthalenyl)-1-propenyl]-benzoic acid.
- 84. A method of identifying retinoid negative hormones, comprising the following steps:
obtaining transfected cells containing a reporter gene transcriptionally responsive to binding of a recombinant retinoid receptor, said recombinant retinoid receptor having at least protein domains located C-terminal to a DNA binding domain of an intact retinoid receptor; measuring a basal level of reporter gene expression in untreated transfected cells, said untreated transfected cells being propagated in the absence of an added retinoid; treating the transfected cells with a retinoid compound to be tested for negative hormone activity; measuring a level of reporter gene expression in treated cells; comparing the levels of reporter gene expression measured in treated cells and untreated cells; and identifying as retinoid negative hormones those retinoid compounds producing a lower level of reporter gene expression in treated cells compared with the basal level of reporter gene expression measured in untreated cells.
- 85. The method of claim 84, wherein the intact retinoid receptor is a retinoic acid receptor selected from the group consisting of RAR-α, RAR-β and RAR-γ.
- 86. The method of claim 84, wherein the intact retinoid receptor is a retinoid X receptor selected from the group consisting of RAR-α, RXR-β and RXR-γ.
- 87. The method of claim 84, wherein the recombinant retinoid receptor is selected from the group consisting of RARs and RXRs.
- 88. The method of claim 84, wherein the recombinant retinoid receptor is a chimeric retinoid receptor having a constitutive transcription activator domain.
- 89. The method of claim 88, wherein the constitutive transcription activator domain comprises a plurality of amino acids having a net negative charge.
- 90. The method of claim 88, wherein the constitutive transcription activator domain has an amino acid sequence of a viral transcription activator domain.
- 91. The method of claim 90, wherein the viral transcription activator domain is the herpes simplex virus VP-16 transcription activator domain.
- 92. The method of claim 88, wherein the constitutive transcription activator domain has a net negative charge, and wherein the recombinant retinoid receptor has deleted therefrom a DNA binding domain.
- 93. The method of claim 84, wherein the recombinant retinoid receptor has a DNA binding domain specific for a cis-regulatory element other than a retinoic acid responsive element.
- 94. The method of claim 93, wherein the cis-regulatory element other than a retinoic acid responsive element is an estrogen responsive element.
- 95. The method of claim 84, wherein the transfected cell is propagated in a growth medium substantially depleted of endogenous retinoids.
- 96. The method of claim 95, wherein the growth medium comprises activated charcoal-extracted serum.
- 97. The method of claim 84, wherein the reporter gene is the luciferase gene and wherein the measuring steps comprise luminometry.
- 98. The method of claim 84, wherein the reporter gene is the β-galactosidase gene and wherein the measuring steps comprise a β-galactosidase assay.
- 99. The method of claim 84, wherein the transfected cell is a transfected mammalian cell.
- 100. The method of claim 99, wherein the transfected mammalian cell is a transiently transfected mammalian cell.
- 101. The method of claim 99, wherein the transfected mammalian cell is a transfected Green monkey cell.
- 102. The method of claim 99, wherein the transfected mammalian cell is a transfected human cell.
- 103. A method of potentiating a pharmacologic activity of a steroid superfamily receptor agonist administered to a mammal, comprising coadministering to the mammal with said steroid superfamily receptor agonist a composition comprising a pharmaceutically effective dose of a retinoid negative hormone to potentiate the pharmacologic activity of the steroid superfamily receptor agonist.
- 104. The method of claim 103, wherein the pharmacologic activity is measurable in a reporter gene trans-activation assay in vitro.
- 105. The method of claim 104, wherein the pharmacologic activity measurable in the reporter gene transactivation assay is anti-AP-1 activity.
- 106. The method of claim 103, wherein the pharmacologic activity is an antiproliferative activity.
- 107. The method of claim 106, wherein the antiproliferative activity is measurable in retinal pigment epithelium.
- 108. The method of claim 103, wherein the steroid superfamily receptor agonist is selected from the group consisting of a retinoid receptor agonist, a vitamin D receptor agonist, a glucocorticoid receptor agonist, a thyroid hormone receptor agonist, a peroxisome proliferator-activated receptor agonist and an estrogen receptor agonist.
- 109. The method of claim 108, wherein the retinoid receptor agonist is an RAR agonist.
- 110. The method of claim 109, wherein the RAR agonist is selected from the group consisting of all-trans-retinoic acid, 13-cis retinoic acid, 4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbonyl]amino]-benzoic acid(Am580), and (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]-benzoic acid (TTNPB).
- 111. The method of claim 108, wherein the retinoid receptor agonist is an RXR agonist.
- 112. The method of claim 111, wherein the RXR agonist is selected from the group consisting of 9-cis-retinoic acid, 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethenyl]-benzoic acid, and 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopropyl]-pyridine-5-carboxylic acid.
- 113. The method of claim 108, wherein the vitamin D receptor agonist is 1,25-dihydroxyvitamin D3.
- 114. The method of claim 108, wherein the glucocorticoid receptor agonist is dexamethasone.
- 115. The method of claim 108, wherein the thyroid hormone receptor agonist is 3,3′,5-triiodothyronine.
- 116. The method of claim 103, wherein the retinoid negative hormone is an RAR-specific retinoid negative hormone.
- 117. The method of claim 116, wherein the RAR-specific retinoid negative hormone has a dissociation constant less than or approximately equal to 30 nM.
- 118. The method of claim 117, wherein the RAR-specific retinoid negative hormone is selected from the group consisting of AGN 193109, AGN 193385, AGN 193389 and AGN 193871.
- 119. The method of claim 103, wherein the composition comprising a pharmaceutically effective dose of a retinoid negative hormone is coadministered at the same time as the steroid superfamily agonist.
- 120. The method of claim 119, wherein the composition comprising a pharmaceutically effective dose of the retinoid negative hormone and the steroid superfamily agonist are combined prior to coadministration.
- 121. The method of claim 103, wherein the composition comprising a pharmaceutically effective dose of the retinoid negative hormone and the steroid superfamily agonist are coadministered as separate compositions.
RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of the three following U.S. applications, each of which was filed as a nonprovisional application and converted to a provisional application by separate petitions filed on Jan. 31, 1996: application Ser. No. 08/522,778, filed Sep. 1, 1995; application Ser. No. 08/522,779, filed Sep. 1, 1995; and application Ser. No. 08/542,648, filed Oct. 13, 1995. The complete disclosures of these related applications is hereby incorporated herein by this reference thereto.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60019015 |
Sep 1995 |
US |
|
60020501 |
Oct 1995 |
US |
|
60064853 |
Sep 1995 |
US |
Divisions (4)
|
Number |
Date |
Country |
Parent |
09447082 |
Nov 1999 |
US |
Child |
09821673 |
Mar 2001 |
US |
Parent |
09222983 |
Dec 1998 |
US |
Child |
09447082 |
Nov 1999 |
US |
Parent |
08871093 |
Jun 1997 |
US |
Child |
09222983 |
Dec 1998 |
US |
Parent |
08613863 |
Mar 1996 |
US |
Child |
08871093 |
Jun 1997 |
US |