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J Med Chem. 2013 Feb 14;56(3):820-31. doi: 10.1021/jm3012917. Epub 2013 Jan 23.

Development of new cyclic plasmin inhibitors with excellent potency and selectivity.

Author information

1
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.

Abstract

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 >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.

PMID:
23294255
DOI:
10.1021/jm3012917
[Indexed for MEDLINE]

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