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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Novel CYP17 inhibitors: synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls.
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Novel CYP17 inhibitors: synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls.

机译：新型CYP17抑制剂：甲氧基和羟基取代的亚甲基咪唑基联苯的合成，生物学评估，构效关系和建模。

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Recently, the steroidal CYP17 inhibitor Abiraterone entered phase II clinical trial for the treatment of androgen-dependent prostate cancer. As 17alpha-hydroxylase-17,20-lyase (CYP17) catalyzes the last step in androgen biosynthesis, inhibition of this target should affect not only testicular but also adrenal androgen formation. Therefore CYP17 inhibitors should be advantageous over existing therapies, for example with GnRH analogues. However, steroidal drugs are known for side effects which are due to affinities for steroid receptors. Therefore we decided to synthesize non-steroidal compounds mimicking the natural CYP17 substrates pregnenolone and progesterone. The synthesis and biological evaluation of a series of 15 novel and highly active non-steroidal CYP17 inhibitors are reported. The compounds were prepared via Suzuki-cross-coupling, Grignard reaction and CDI-assisted S(N)t-reaction with imidazole and their inhibitory activity was examined with recombinant human CYP17 expressed in Escherichia coli. Promising compounds were further tested for their selectivity against the hepatic enzyme CYP3A4 and the glucocorticoid-forming enzyme CYP11B1. All compounds turned out to be potent CYP17 inhibitors. The most active compounds 7 and 8 were much more active than Ketoconazole showing activity comparable to Abiraterone (IC(50) values of 90 and 52nM vs. 72nM). Most compounds also showed higher selectivities than Ketoconazole, but turned out to be less selective than Abiraterone. Docking studies using our CYP17 protein model were performed with selected compounds to study the interactions between the inhibitors and the amino acid residues of the active site.
机译：最近，甾体CYP17抑制剂阿比特龙进入了II期临床试验，用于治疗雄激素依赖性前列腺癌。由于17α-羟化酶-17,20-裂合酶（CYP17）催化雄激素生物合成的最后一步，对该靶标的抑制不仅会影响睾丸，还会影响肾上腺雄激素的形成。因此，CYP17抑制剂应优于现有疗法，例如使用GnRH类似物。然而，由于类固醇受体的亲和力，类固醇药物的副作用是已知的。因此，我们决定合成模拟天然CYP17底物孕烯醇酮和孕酮的非甾体化合物。报道了一系列15种新型和高活性非甾体CYP17抑制剂的合成和生物学评估。通过铃木交叉偶联，格利雅反应和与咪唑的CDI辅助S（N）t反应制备化合物，并用在大肠杆菌中表达的重组人CYP17检测其抑制活性。进一步测试了有前途的化合物对肝酶CYP3A4和形成糖皮质激素的酶CYP11B1的选择性。事实证明所有化合物都是有效的CYP17抑制剂。活性最高的化合物7和8比酮康唑具有更高的活性，显示的活性与阿比特龙相当（IC（50）值为90和52nM，而72nM）。大多数化合物还显示出比酮康唑更高的选择性，但事实证明其选择性不如阿比特龙。使用我们的CYP17蛋白模型对接研究与选定的化合物一起进行，以研究抑制剂与活性位点氨基酸残基之间的相互作用。

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