| Autor: |
Grese, T. A., Cho, S., Finley, D. R., Godfrey, A. G., Jones, C. D., Lugar, C. W., III, Martin, M. J., Matsumoto, K., Pennington, L. D., Winter, M. A., Adrian, M. D., Cole, H. W., Magee, D. E., Phillips, D. L., Rowley, E. R., Short, L. L., Glasebrook, A. L., Bryant, H. U. |
| Zdroj: |
Journal of Medicinal Chemistry; January 17, 1997, Vol. 40 Issue: 2 p146-167, 22p |
| Abstrakt: |
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. |
| Databáze: |
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