5-((4-氨基哌啶-1-基)甲基)吡咯并三嗪，EGFR和HER2蛋白酪氨酸激酶的双重抑制剂。
5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
作者信息
Mastalerz Harold, Chang Ming, Chen Ping, Fink Brian E, Gavai Ashvinikumar, Han Wen-Ching, Johnson Walter, Langley David, Lee Francis Y, Leavitt Kenneth, Marathe Punit, Norris Derek, Oppenheimer Simone, Sleczka Bogdan, Tarrant James, Tokarski John S, Vite Gregory D, Vyas Dolatrai M, Wong Henry, Wong Tai W, Zhang Hongjian, Zhang Guifen
机构信息
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-1951, USA.
出版信息
Bioorg Med Chem Lett. 2007 Sep 1;17(17):4947-54. doi: 10.1016/j.bmcl.2007.06.019. Epub 2007 Jun 10.
Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
发现带有5-((4-氨基哌啶-1-基)甲基)增溶基团的吡咯并三嗪双EGFR/HER2激酶抑制剂优于具有先前报道的C-5增溶基团的类似物。开发了用于平行合成带有新增溶基团的C-4类似物的新合成方法。在肿瘤异种移植模型中评估了有趣的新先导化合物，发现C-4氨基氟苯并吲唑1c表现出最佳的抗肿瘤活性。据推测，该增溶基团延伸到ATP结合口袋的核糖-磷酸部分，并增强了抑制剂的结合亲和力。
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