Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.


New macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin.

DOI: 10.1021/acs.jmedchem.6b00606

Cite this paper

@article{Hinkes2016OptimizationOC, title={Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.}, author={Stefan Hinkes and Andr{\'e} Wuttke and Sebastian Martin Saupe and T. G. Ivanova and Sebastian A. Wagner and Anna Kn{\"{o}rlein and Andreas von Heine and Gerhard Klebe and Torsten Steinmetzer}, journal={Journal of medicinal chemistry}, year={2016}, volume={59 13}, pages={6370-86} }