Abdelsamie Ahmed S, Bey Emmanuel, Hanke Nina, Empting Martin, Hartmann Rolf W, Frotscher Martin
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany.
ElexoPharm GmbH, Campus C11, D-66123 Saarbrücken, Germany.
Eur J Med Chem. 2014 Jul 23;82:394-406. doi: 10.1016/j.ejmech.2014.05.074. Epub 2014 Jun 3.
Estradiol is the most potent estrogen in humans. It is known to be involved in the development and proliferation of estrogen dependent diseases such as breast cancer and endometriosis. The last step of its biosynthesis is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β- HSD1) which consequently is a promising target for the treatment of these diseases. Recently, we reported on bicyclic substituted hydroxyphenylmethanones as potent inhibitors of 17β-HSD1. The present study focuses on rational structural modifications in this compound class with the aim of gaining more insight into its structure-activity relationship (SAR). (4-Hydroxyphenyl)-(5-(3-hydroxyphenylsulfanyl)-thiophen-2-yl)methanone (25) was discovered as a member of a novel potent class of human 17β-HSD1 inhibitors. Computational methods were used to elucidate its interactions with the target protein. The compound showed activity also towards the murine 17β-HSD1 enzyme and thus is a starting point for the design of compounds suitable for evaluation in an animal disease model.
雌二醇是人体内活性最强的雌激素。已知它参与雌激素依赖性疾病（如乳腺癌和子宫内膜异位症）的发展和增殖。其生物合成的最后一步由1型17β - 羟基类固醇脱氢酶（17β - HSD1）催化，因此该酶是治疗这些疾病的一个有前景的靶点。最近，我们报道了双环取代的羟基苯基甲酮作为17β - HSD1的强效抑制剂。本研究聚焦于对该类化合物进行合理的结构修饰，旨在更深入了解其构效关系（SAR）。（4 - 羟基苯基） - （5 - （3 - 羟基苯基硫烷基） - 噻吩 - 2 - 基）甲酮（25）被发现是一类新型强效人类17β - HSD1抑制剂中的一员。采用计算方法阐明其与靶蛋白的相互作用。该化合物对小鼠17β - HSD1酶也有活性，因此是设计适合在动物疾病模型中进行评估的化合物的起点。
