EphB3 受体酪氨酸激酶抑制剂的构效关系研究。
Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors.
机构信息
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
出版信息
Bioorg Med Chem Lett. 2009 Nov 1;19(21):6122-6. doi: 10.1016/j.bmcl.2009.09.010. Epub 2009 Sep 9.
Abstract
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 288 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.
摘要
一项关于吡唑并[1,5-a]吡啶的 2-氯苯甲酰胺衍生物的构效关系研究表明，通过保留 2-氯苯甲酰胺并在吡唑并[1,5-a]吡啶的 5-位引入苯基或小供电子取代基，可以提高 EphB3 激酶抑制活性。此外，用咪唑并[1,2-a]吡啶替代吡唑并[1,5-a]吡啶也能很好地耐受，并导致小鼠肝微粒体稳定性增强。两种杂环系列的 EphB3 抑制的构效关系相似。代表性类似物在细胞培养中也显示出激酶抑制活性。一个类似物（32，LDN-211904）也对 288 种激酶的抑制活性进行了分析，发现对酪氨酸激酶具有很高的选择性。总的来说，这些研究为研究 EphB3 受体的体外、细胞和潜在体内激酶依赖性功能提供了有用的分子探针。
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