title: A new strategy for the development of highly potent and selective plasmin inhibitors.
abstract: A new structure-based strategy for the design of potent and selective plasmin inhibitors was developed. These compounds could be prepared by cyclizations between the P3 and P2 amino acid residues of substrate-analogue inhibitors using metathesis or a copper-catalyzed azide alkyne cycloaddition in combination with standard peptide couplings. The most potent bis-triazole derivative 10 inhibits plasmin and plasma kallikrein with K(i) of 0.77 and 2.4 nM, respectively, whereas it has poor activity against the related trypsin-like serine proteases thrombin, factor Xa, or activated protein C. Modeling experiments revealed that inhibitor 10 adopts a compact and rigid structure that fits well into the relatively open active site of plasmin and plasma kallikrein, while it is rejected from sterically demanding residues present in loops of the other enzymes. These results from modeling confirm the selectivity profile found for inhibitor 10 in enzyme kinetic studies. Such compounds might be useful lead structures for the development of new antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce bleeding complications.
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: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000595:Amino Acid Sequence; D000933:Antifibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry; D057075:Enzyme Assays; D005341:Fibrinolysin / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000933:Antifibrinolytic Agents; D004151:Dipeptides; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D014230:Triazoles; D005341:Fibrinolysin