Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
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DOI：
10.1016/j.bmc.2013.04.056
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发表时间：
2013-07-15
影响因子：
3.5
通讯作者：
Soga, Tsunehiko
中科院分区：
文献类型：
--
作者：
Miyazaki, Masaki;Naito, Hiroyuki;Soga, Tsunehiko
我们已经发现并报道了具有二氢咪唑并噻唑骨架的有效的p53-MDM 2相互作用抑制剂。我们的先导化合物在体外表现出很强的活性，但由于代谢稳定性低，在体内没有表现出抗肿瘤功效。为了获得口服活性化合物，我们通过改善理化性质对我们的先导化合物进行了进一步优化。因此，我们通过在吡咯烷的C-2取代基上引入烷基来防止代谢，并修饰脯氨酸基序的末端取代基来改善溶解性，从而提供了最佳化合物。这些最佳化合物在使用具有野生型p53的MV 4 -11细胞的异种移植模型上口服给药时表现出良好的PK特征和显著的抗肿瘤功效。(C)2013爱思唯尔有限公司保留所有权利。
We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53. (C) 2013 Elsevier Ltd. All rights reserved.