Syntheses of various bis-ortho-alkoxy-para-piperazineanilino-pyrimidines and -triazines of KRCA-0008 analogs are described and their structure-activity-relationship to anaplastic lymphoma kinase (ALK) is discussed. 5-trifluoromethyl-2,4-pyrimidine analog (2) seems to be most potent in both biochemical and cellular assay in this study, however it shows inferior mice xenograft activity to Crizotinib presumably due to its sub-optimal PK parameters. 4,6-disubstituted pyrimidine and 2,4-disubstituted triazine derivatives of KRCA-0008 are less potent or inactive to ALK wt., and this observation is explained with their molecular modeling compared to KRCA-0008.

译文

描述了KRCA-0008类似物的各种双邻位烷氧基-对哌嗪苯胺基嘧啶和三嗪的合成,并讨论了它们与间变性淋巴瘤激酶 (ALK) 的构效关系。在这项研究中,5-三氟甲基-2,4-嘧啶类似物 (2) 在生化和细胞测定中似乎最有效,但是它显示出克唑替尼的小鼠异种移植活性较差,可能是由于其PK参数次优。KRCA-0008的4,6-二取代嘧啶和2,4-二取代三嗪衍生物对alkwt.的效力较低或无活性,并且与KRCA-0008相比,用它们的分子模型解释了这一观察结果。

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