Design, Synthesis, Biological Evaluation and Pharmacokinetics of Bis(hydroxyphenyl) substituted Azoles, Thiophenes, Benzenes, and Aza-Benzenes as Potent and Selective Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1)

被引：102

作者：

Bey, Emmanuel ^{[1
]}

Marchais-Oberwinkler, Sandrine ^{[1
]}

Werth, Ruth ^{[1
]}

Al-Soud, Yaseen A. ^{[1
]}

Kruchten, Patricia ^{[1
]}

Oster, Alexander ^{[1
]}

Frotscher, Martin ^{[1
]}

Birk, Barbara ^{[2
]}

Hartmann, Rolf W. ^{[1
]}

机构：

[1] Univ Saarland, D-66041 Saarbrucken, Germany

[2] Pharmacelsus CRO, D-66123 Saarbrucken, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 21期

关键词：

D O I：

10.1021/jm8006917

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

17 beta-Estradiol (E2), the most potent female sex hormone, stimulates the growth of mammary tumors and endometriosis via activation of the estrogen receptor alpha (ER alpha). 17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1), which is responsible for the catalytic reduction of the weakly active estrogen estrone (E I) into E2, is therefore discussed as a novel drug target. Recently, we have discovered a 2,5-bis(hydroxyphenyl) oxazole to be a potent inhibitor of 17 beta-HSD1. In this paper, further structural optimizations were performed: 39 bis(hydroxyphenyl) azoles, thiophenes, benzenes, and aza-benzenes were synthesized and their biological properties were evaluated. The most promising compounds of this study show enhanced IC50 values in the low nanomolar range, a high selectivity toward 17 beta-HSD2, a low binding affinity to ER alpha, a good metabolic stability in rat liver microsomes, and a reasonable pharmacokinetic profile after peroral application. Calculation of the molecular electrostatic potentials revealed a correlation between 17 beta-HSD1 inhibition and the electron density distribution.

引用

页码：6725 / 6739

页数：15

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[1] Overview and new strategies in metastatic breast cancer (MBC) for treatment of tamoxifen-resistant patients [J].