Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17).: Part I:: Heterocyclic modifications of the core structure
Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17).: Part I:: Heterocyclic modifications of the core structure
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DOI：
10.1016/j.bmc.2007.10.094
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发表时间：
2008-02-15
影响因子：
3.5
通讯作者：
Hartmann, Rolf W.
中科院分区：
文献类型：
--
作者：
Jagusch, Carsten;Negri, Matthias;Hartmann, Rolf W.
通过 Suzuki 和 S-N 反应制备了新的化学实体作为 CYP17 的 AC 环底物模拟物。使用在大肠杆菌中表达的人CYP17测试合成的化合物1-31的活性。测试了有前景的化合物对肝 CYP 酶（3A4、2D6、1A2、2C9、2C19、2B6）的选择性。在大鼠中进一步检查了两种有效抑制剂（27，IC50 = 373 nM/28，IC50 = 953 nM）对血浆睾酮水平及其药代动力学特性的影响。化合物 28 的活性与阿比特龙相似，并显示出更好的药代动力学特性（更高的生物利用度，t(1/2) 9.5 小时 vs 1.6 小时）。对接研究揭示了两种不同于底物和类固醇抑制剂之一的新结合模式。 (c) 2007 Elsevier Ltd. 保留所有权利。
Novel chemical entities were prepared via Suzuki and S-N reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6). Two potent inhibitors (27, IC50 = 373 nM/28, IC50 = 953 nM) were further examined in rats regarding their effects on plasma testosterone levels and their pharmacokinetic properties. Compound 28 was similarly active as abiraterone and showed better pharmacokinetic properties (higher bioavailability, t(1/2) 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors. (c) 2007 Elsevier Ltd. All rights reserved.