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)
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)
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DOI：
10.1021/jm8006917
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发表时间：
2008-11-13
影响因子：
7.3
通讯作者：
Hartmann, Rolf W.
中科院分区：
文献类型：
--
作者：
Bey, Emmanuel;Marchais-Oberwinkler, Sandrine;Hartmann, Rolf W.
17 β-雌二醇 (E2) 是最有效的女性性激素，通过激活雌激素受体 α (ER α) 刺激乳腺肿瘤和子宫内膜异位症的生长。 17β-羟基类固醇脱氢酶 1 型 (17β-HSD1) 负责将弱活性雌激素雌酮 (E I) 催化还原为 E2，因此被讨论为新型药物靶点。最近，我们发现 2,5-双（羟基苯基）恶唑是 17 beta-HSD1 的有效抑制剂。本文进行了进一步的结构优化：合成了39种双(羟基苯基)唑类、噻吩类、苯类和氮杂苯类化合物，并评价了它们的生物学性质。本研究中最有前途的化合物显示出在低纳摩尔范围内增强的IC50值、对17β-HSD2的高选择性、对ERα的低结合亲和力、在大鼠肝微粒体中良好的代谢稳定性以及口服应用后合理的药代动力学特征。分子静电势的计算揭示了 17 beta-HSD1 抑制与电子密度分布之间的相关性。
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.