Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines

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• 作者：Stefan Hinkes ; André Wuttke ; Sebastian M. Saupe ; Teodora Ivanova ; Sebastian Wagner ; Anna Knörlein ; Andreas Heine ; Gerhard Klebe ; Torsten Steinmetzer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6370-6386
• 全文大小：773K
• 年卷期：0
• ISSN：1520-4804

文摘

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.