Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors.
Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors.
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DOI：
10.1016/j.bmcl.2009.09.010
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发表时间：
2009-11-01
影响因子：
2.7
通讯作者：
Cuny GD
中科院分区：
文献类型：
--
作者：
Qiao L;Choi S;Case A;Gainer TG;Seyb K;Glicksman MA;Lo DC;Stein RL;Cuny GD
对吡唑啉[1,5- A]吡啶衍生物的构效关系研究表明，保留2-氯苯胺并在吡唑啉[1,5- A]吡啶的5位上引入苯基或小的给电子取代基可以提高EphB3激酶抑制活性。此外，咪唑[1,2-a]吡啶替代吡唑[1,5-a]吡啶耐受性良好，可增强小鼠肝微粒体的稳定性。两个杂环系对EphB3抑制的构效关系相似。在细胞培养中也证明了具有代表性的类似物的激酶抑制活性。一个类似物（32,LDN-211904）也对288种激酶的抑制活性进行了分析，并发现对酪氨酸激酶具有很强的选择性。总的来说，这些研究为研究EphB3受体的体外、细胞和体内激酶依赖功能提供了有用的分子探针。
A structure-activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5-a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure-activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN-211904) was also profiled for inhibitory activity against a panel of two hundred and eighty eight kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor.
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