- Synthesis and binding affinities of fluoroalkylated raloxifenes
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Three fluoroalkylated derivatives (1-3) of the selective estrogen receptor modulator (SERM), raloxifene, have been synthesized. The key step in the synthesis is the C-C bond formation of benzo[b]thiophene and a substituted phenyl group (ring C) using a Stille reaction. The in vitro binding affinities of the substituted raloxifenes 1-3 are 45, 60, 89%, respectively, relative to the affinity of estradiol, which is higher than the affinity of raloxifene itself (25%). When labeled with the positron-emitting radionuclide, these compounds might be useful as PET imaging agents for estrogen receptor-positive breast tumors.
- Lee, Kyo Chul,Moon, Byung Seok,Lee, Jae Hak,Chung, Kyoo-Hyun,Katzenellenbogen, John A.,Chi, Dae Yoon
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p. 3649 - 3658
(2007/10/03)
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- Synergistic methodologies for the synthesis of 3-aroyl-2- arylbenzo[b]thiophene-based selective estrogen receptor modulators. Two concise syntheses of raloxifene
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Difunctionalized benzo[b]thiophene intermediates are prepared which allow fully independent elaboration of the 2-aryl position or the tether position of benzo[b]thiophene-based selective estrogen receptor modulators (SERMs). Two concise syntheses of the SERM raloxifene (Evista) are presented.
- Bradley, David A.,Godfrey, Alexander G.,Schmid, Christopher R.
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p. 5155 - 5159
(2007/10/03)
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- Structure-activity relationships of selective estrogen receptor modulators: Modifications to the 2-arylbenzothiophene core of raloxifene
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The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'- substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7- position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6- carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.
- Grese, Timothy A.,Cho, Stephen,Finley, Don R.,Godfrey, Alexander G.,Jones, Charles D.,Lugar III, Charles W.,Martin, Michael J.,Matsumoto, Ken,Pennington, Lewis D.,Winter, Mark A.,Adrian, M. Dee,Cole, Harlan W.,Magee, David E.,Phillips, D. Lynn,Rowley, Ellen R.,Short, Lorri L.,Glasebrook, Andrew L.,Bryant, Henry U.
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p. 146 - 167
(2007/10/03)
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- Benzothiphene derivatives for treating resistant tumors
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This invention provides a series of substituted benzo[b]thiophenes useful in reversing multidrug resistance in a resistant neoplasm. The present invention also provides methods for reversing the multidrug resistance in a resistant neoplasm by treating a mammal in need of said treatment with a substituted benzothiophene. This invention also provides methods for treating neoplasms in a mammal which comprises administering to a mammal in need of this treatment a substituted benzothiophene in combination with an oncolytic agent.
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