5eg4

Publication Abstract from PubMed

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.

Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.,Hinkes S, Wuttke A, Saupe SM, Ivanova T, Wagner S, Knorlein A, Heine A, Klebe G, Steinmetzer T J Med Chem. 2016 Jun 17. PMID:27280436^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.