Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
J Med Chem. 2013 Feb 14;56(3):820-31. doi: 10.1021/jm3012917. Epub 2013 Jan 23.
The trypsin-like serine protease plasmin is a target for the development of antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce excessive blood loss. The optimization of our recently described substrate-analogue plasmin inhibitors, which were cyclized between their P3 and P2 side chains, provided a new series with improved efficacy and excellent selectivity. The most potent inhibitor 8 binds to plasmin with an inhibition constant of 0.2 nM, whereas K(i) values >1 μM were determined for nearly all other tested trypsin-like serine proteases, with the exception of trypsin, which is also inhibited in the nanomolar range. Docking studies revealed a potential binding mode in the widely open active site of plasmin that explains the strong potency and selectivity profile of these inhibitors. The dialkylated piperazine-linker segment contributes to an excellent solubility of all analogues. Based on their overall profile the presented inhibitors are well suited for further development as injectable antifibrinolytic drugs.
胰蛋白酶样丝氨酸蛋白酶纤溶酶是开发抗纤维蛋白溶解药物的靶标，用于体外循环心脏手术或器官移植，以减少过度失血。最近描述的底物类似物纤溶酶抑制剂的优化，在其 P3 和 P2 侧链之间环化，提供了一系列具有改进疗效和优异选择性的新化合物。最有效的抑制剂 8 与纤溶酶的结合抑制常数为 0.2 nM，而对于几乎所有其他测试的胰蛋白酶样丝氨酸蛋白酶，K(i)值均>1 μM，除了纤溶酶，其也在纳摩尔范围内被抑制。对接研究揭示了纤溶酶广泛开放的活性位点中的潜在结合模式，解释了这些抑制剂的强大效力和选择性特征。二烷基化哌嗪连接片段有助于所有类似物具有优异的溶解度。基于它们的整体特征，所呈现的抑制剂非常适合进一步开发为可注射的抗纤维蛋白溶解药物。
