title: Development of new cyclic plasmin inhibitors with excellent potency and selectivity.
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.
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Saupe
authors.forename: Stephanie
authors.initials: S
authors.lastname: Leubner
authors.forename: Michael
authors.initials: M
authors.lastname: Betz
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000933:Antifibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular
chemical_list: D000933:Antifibrinolytic Agents