Pharmaceutical and Medicinal Chemistry, Saarland University, & the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2 3, P.O. Box 151150, 66123 Saarbrücken, Germany.
ChemMedChem. 2011 Mar 7;6(3):476-87. doi: 10.1002/cmdc.201000457. Epub 2011 Feb 17.
An attractive target that has still to be explored for the treatment of estrogen-dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β-HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen-dependent pathologies. Recently, we reported a new class of highly active and selective 17β-HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty-nine novel inhibitors were synthesized and evaluated for 17β-HSD1 inhibition in a cell-free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC50 values of 12 nM (cell-free assay) and 78 nM (cellular assay), high selectivity for 17β-HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein-ligand interactions of this compound with 17β-HSD1.
作为治疗雌激素依赖性疾病（如乳腺癌和子宫内膜异位症）的潜在目标，负责雌二醇（E2）生物合成最后一步的酶——17β-羟类固醇脱氢酶 1 型（17β-HSD1）仍有待探索。它催化将弱活性的雌酮（E1）还原为 E2，E2 是人体内最有效的雌激素。抑制 17β-HSD1 可降低细胞内 E2 浓度，因此成为治疗雌激素依赖性病理的靶点。最近，我们报道了一类新型高活性和选择性的 17β-HSD1 抑制剂：双环取代的羟苯基甲酮。在此，我们进一步描述了双环部分的结构变化，特别是重点研究了其羟基功能的交换。合成了 29 种新型抑制剂，并在无细胞和细胞测定中评估了它们对 17β-HSD1 的抑制作用、对 17β-HSD2 和雌激素受体（ER）α和β的选择性以及代谢稳定性。最佳化合物在无细胞测定中的 IC50 值为 12 nM，在细胞测定中的 IC50 值为 78 nM，对 17β-HSD1 具有高选择性，且代谢稳定性良好。分子对接研究深入了解了该化合物与 17β-HSD1 的蛋白-配体相互作用。
