Fujimoto Jun, Hirayama Takaharu, Hirata Yasuhiro, Hikichi Yukiko, Murai Saomi, Hasegawa Maki, Hasegawa Yuka, Yonemori Kazuko, Hata Akito, Aoyama Kazunobu, Cary Douglas R
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem. 2017 Jun 15;25(12):3018-3033. doi: 10.1016/j.bmc.2017.03.049. Epub 2017 Mar 30.
In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC: 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.
本文讨论了围绕基于吡啶基丙烯酰胺的先导化合物（1）开展的合成研究，该研究利用了由CDK8对接模型指导的基于结构的药物设计。将侧链4-氟苯基修饰为各种杂芳环，旨在与近端氨基酸相互作用，然后以取代吗啉环为目标，以降低时间依赖性CYP3A4抑制的可能性。这些努力产生了化合物4k，其具有增强的CDK8抑制活性，且没有明显的时间依赖性CYP3A4抑制潜力（CDK8 IC：2.5nM；CYP3A4 TDI：99%的化合物残留）。发现化合物4k具有高度选择性的激酶抑制谱，并且还显示出良好的药代动力学特征。在RPMI8226小鼠异种移植模型中，口服给予4k（15mg/kg，每日两次，持续2周）可抑制肿瘤生长（T/C 29%）。
