Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution |
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Authors: | Gauthier Sylvain Cloutier Julie Dory Yves L Favre Alexandre Mailhot Josée Ouellet Carl Schwerdtfeger Annette Mérand Yves Martel Céline Simard Jacques Labrie Fernand |
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Institution: | Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), Québec G1V 4G2, Canada. sylvain.gauthier@crchul.ulaval.ca |
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Abstract: | EM-652 (acolbifene) analogs have been synthesized as selective estrogen receptor modulators. Substitution on the nitrogen atom of these 2H-1-benzopyran derivatives has been studied for its influence on antiestrogenic activity. Binding to the rat estrogen receptor, inhibition of estradiol-stimulated proliferation of T-47D breast cancer cells, as well as antiuterotrophic and uterotrophic activities in ovariectomized mice have been evaluated. 2H-1-Benzopyran 1b (EM-343, racemic form of EM-652), which contains a piperidine ring, shows the best pharmacological profile; RBA = 380, IC50 value = 0.110 nM (in T-47D cells), as well as 63% and 84% antiuterotrophic inhibitions at the 7.5 and 75 nmol doses, respectively. |
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