Institut de Chimie des Substances Naturelles, Centre de Recherche de Gif, UPR 2301, CNRS , Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
J Med Chem. 2013 Dec 12;56(23):9569-85. doi: 10.1021/jm401049v. Epub 2013 Nov 19.
A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j-l) demonstrated high inhibitory potencies with Kis in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10(-6) M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3.
一系列 3,5-二芳基-1H-吡咯并[2,3-b]吡啶被合成并评估了它们对 DYRKIA 激酶的体外抑制活性。在芳基部分具有羟基的衍生物（2c、2j-l）表现出高的抑制活性，其 Kis 值在纳摩尔范围内。它们的甲氧基类似物的活性低至 100 倍。在 ATP 结合位点的对接研究表明，这些化合物通过与肽骨架的多个氢键网络紧密结合到该位点。在 10(-6) M 时，没有一种活性化合物对 KB 细胞表现出细胞毒性。激酶谱分析显示，化合物 2j 对 DYRK1A 的选择性是 DYRK2 和 DYRK3 的 2 倍。
