Design and Optimization of a Series of 1-Sulfonylpyrazolo[4,3-b]pyridines as Selective c-Met Inhibitors
Design and Optimization of a Series of 1-Sulfonylpyrazolo[4,3-b]pyridines as Selective c-Met Inhibitors
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一系列 1-磺酰基吡唑并[4,3-b]吡啶类选择性 c-Met 抑制剂的设计和优化
DOI：
10.1021/jm502018y
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发表时间：
2015-03-12
影响因子：
7.3
通讯作者：
Shen, Jingkang
中科院分区：
文献类型：
--
作者：
Ma, Yuchi;Sun, Guangqiang;Shen, Jingkang
由于c-Met在许多癌细胞中异常活化，它已成为靶向癌症治疗的一个有吸引力的靶标。为了确定高效和选择性的c-Met抑制剂，我们首先分析了报道的hit 7的效力和体外代谢稳定性。通过合理设计，发现了一种具有改进DMPK性能的新型磺酰基吡唑[4,3-b]吡啶9。进一步细化pi-pi堆叠相互作用和溶剂可接近的极性部分导致了一系列高效和选择性的I型c-Met抑制剂。在体外和体内药理及药代动力学研究的基础上，化合物46被选为进一步开发抗癌药物的临床前候选药物。
c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of pi-pi stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.