Faculty of Science, Chemistry Department, Islamic University of Gaza, Gaza Strip, Palestine.
J Med Chem. 2012 Jan 26;55(2):961-5. doi: 10.1021/jm201391u. Epub 2012 Jan 17.
In the course of searching for new p38α MAP kinase inhibitors, we found that the regioisomeric switch from 3-(4-fluorophenyl)-4-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine to 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine led to an almost complete loss of p38α inhibition, but they showed activity against important cancer kinases. Among the tested derivatives, 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazol-5-amine (6a) exhibited the best activity, with IC(50) in the nanomolar range against Src, B-Raf wt, B-Raf V600E, EGFRs, and VEGFR-2, making it a good lead for novel anticancer programs.
在寻找新型 p38α MAP 激酶抑制剂的过程中，我们发现从 3-(4-氟苯基)-4-(吡啶-4-基)-1-(芳基)-1H-吡唑-5-胺到 4-(4-氟苯基)-3-(吡啶-4-基)-1-(芳基)-1H-吡唑-5-胺的区域异构体转换几乎完全丧失了对 p38α 的抑制作用，但它们对重要的癌症激酶表现出活性。在所测试的衍生物中，4-(4-氟苯基)-3-(吡啶-4-基)-1-(2,4,6-三氯苯基)-1H-吡唑-5-胺（6a）表现出最好的活性，对Src、B-Raf wt、B-Raf V600E、EGFRs 和 VEGFR-2 的 IC50 值均在纳摩尔范围内，使其成为新型抗癌方案的良好先导化合物。
