Abdelsamie Ahmed S, Bey Emmanuel, Gargano Emanuele M, van Koppen Chris J, Empting Martin, Frotscher Martin
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany.
ElexoPharm GmbH, Campus A12, D-66123 Saarbrücken, Germany.
Eur J Med Chem. 2015 Oct 20;103:56-68. doi: 10.1016/j.ejmech.2015.08.030. Epub 2015 Aug 18.
17β-Estradiol (E2), the most potent human estrogen, is known to be involved in the etiology of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenylmethanones (BSHs) display high inhibitory potency towards human 17β-HSD1, but marginal activity towards rodent 17β-HSD1, precluding a proof of principle study in an animal endometriosis model. The aim of this work was to perform structural optimizations in the BSHs class to enhance inhibitory activity against rodent (mouse and rat) 17β-HSD1 while maintaining activity against the human enzyme. The introduction of fluorine atoms on the benzoyl moiety resulted in compounds with the desired properties. Molecular docking and homology modeling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17β-HSD1 up to date (IC₅₀ = 2 nM and 97 nM, respectively).
17β - 雌二醇（E2）是人体内活性最强的雌激素，已知其与雌激素依赖性疾病（如乳腺癌和子宫内膜异位症）的病因有关。17β - 羟类固醇脱氢酶1型（17β - HSD1）催化E2生物合成的最后一步，因此是治疗雌激素依赖性疾病的一个有前景的靶点。先前描述的双环取代羟基苯甲酮（BSHs）对人17β - HSD1显示出高抑制活性，但对啮齿动物17β - HSD1的活性微弱，这使得在动物子宫内膜异位症模型中进行原理验证研究受到阻碍。这项工作的目的是对BSHs类进行结构优化，以增强对啮齿动物（小鼠和大鼠）17β - HSD1的抑制活性，同时保持对人酶的活性。在苯甲酰部分引入氟原子得到了具有所需性质的化合物。应用分子对接和同源建模来阐明结合模式和种间活性差异。化合物33是迄今为止对人和大鼠17β - HSD1均最有效的抑制剂（IC₅₀分别为2 nM和97 nM）。
