Development of New Cyclic Plasmin Inhibitors with Excellent Potency and Selectivity

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 Ki 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.