Bey Emmanuel, Marchais-Oberwinkler Sandrine, Negri Matthias, Kruchten Patricia, Oster Alexander, Klein Tobias, Spadaro Alessandro, Werth Ruth, Frotscher Martin, Birk Barbara, Hartmann Rolf W
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrucken, Germany.
J Med Chem. 2009 Nov 12;52(21):6724-43. doi: 10.1021/jm901195w.
17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is responsible for the catalytic reduction of weakly active E1 to highly potent E2. E2 stimulates the proliferation of hormone-dependent diseases via activation of the estrogen receptor alpha (ERalpha). Because of the overexpression of 17beta-HSD1 in mammary tumors, this enzyme should be an attractive target for the treatment of estrogen-dependent pathologies. Recently, we have reported on a series of potent 17beta-HSD1 inhibitors: bis(hydroxyphenyl) azoles, thiophenes, and benzenes. In this paper, different substituents are introduced into the core structure and the biological properties of the corresponding inhibitors are evaluated. Computational methods and analysis of different X-rays of 17beta-HSD1 lead to identification of two different binding modes for these inhibitors. The fluorine compound 23 exhibits an IC(50) of 8 nM and is the most potent nonsteroidal inhibitor described so far. It also shows a high selectivity (17beta-HSD2, ERalpha) and excellent pharmacokinetic properties after peroral application to rats.
17β-羟类固醇脱氢酶1型（17β-HSD1）负责将活性较弱的雌酮（E1）催化还原为活性较强的雌二醇（E2）。E2通过激活雌激素受体α（ERα）刺激激素依赖性疾病的细胞增殖。由于17β-HSD1在乳腺肿瘤中过表达，该酶应是治疗雌激素依赖性疾病的一个有吸引力的靶点。最近，我们报道了一系列有效的17β-HSD1抑制剂：双（羟苯基）唑类、噻吩类和苯类。本文将不同的取代基引入核心结构，并评估相应抑制剂的生物学特性。通过计算方法和对17β-HSD1不同X射线的分析，确定了这些抑制剂的两种不同结合模式。氟化合物23的半数抑制浓度（IC50）为8 nM，是迄今为止描述的最有效的非甾体抑制剂。经口给予大鼠后，它还表现出高选择性（针对17β-HSD2、ERα）和优异的药代动力学特性。
