Development of New Cyclic Plasmin Inhibitors with Excellent Potency and Selectivity

作者：Saupe Sebastian M; Leubner Stephanie; Betz Michael; Klebe Gerhard; Steinmetzer Torsten^*

来源：Journal of Medicinal Chemistry, 2013, 56(3): 820-831.

DOI：10.1021/jm3012917

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 %26gt;1 mu M 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.

• 出版日期2013-2-14