Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, D-66041 Saarbrücken, Germany.
J Med Chem. 2012 Apr 12;55(7):3307-18. doi: 10.1021/jm201735j. Epub 2012 Mar 16.
The reduction of estrone to estradiol, the most potent estrogen in human, is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). A promising approach for the treatment of estrogen-dependent diseases is the reduction of intracellular estradiol formation by inhibition of 17β-HSD1. For the species-specific optimization of the (hydroxyphenyl)naphthols, a combinatorial approach was applied and enhanced by a focused synthesis that resulted in the aromatic-substituted (hydroxyphenyl)naphthol sulfonamides. Rigidification of 12 led to the 4-indolylsulfonamide 30, which is a highly active and selective human 17β-HSD1 inhibitor, as well as a highly potent and selective inhibitor of 17β-HSD1 from Callithrix jacchus. It shows no affinity to the estrogen receptors α and β and good intracellular activity (T47D). Thus, compound 30 shows good properties for further ADMET studies and might be a candidate for the in vivo proof of concept in C. jacchus.
雌酮向人体内最强雌激素雌二醇的转化是由 17β-羟甾脱氢酶 1 型（17β-HSD1）催化的。通过抑制 17β-HSD1 减少细胞内雌二醇的形成，是治疗雌激素依赖性疾病的一种很有前途的方法。为了对（羟基苯基）萘酚进行种属特异性优化，应用了组合方法，并通过重点合成进行了增强，得到了取代芳基（羟基苯基）萘酚磺酰胺。12 的刚性化导致了 4-吲哚基磺酰胺 30 的产生，它是一种高活性和选择性的人 17β-HSD1 抑制剂，也是来自 Callithrix jacchus 的 17β-HSD1 的高活性和选择性抑制剂。它对雌激素受体 α 和 β 没有亲和力，并且具有良好的细胞内活性（T47D）。因此，化合物 30 具有进一步进行 ADMET 研究的良好特性，并且可能成为在 C. jacchus 中体内概念验证的候选药物。
