title: Thrombin inhibitors as antithrombotic agents: the importance of rapid inhibition.
abstract: For use as an antithrombotic agent, a thrombin inhibitor must be potent and specific, i.e., it should not significantly inhibit the proteases of the anticoagulation (activated protein C) and fibrinolytic systems (plasminogen activator and plasmin). Previous evaluation of potency and specificity has been based on inhibition constants (Ki values). However, consideration of the kinetic parameters for natural plasma serine protease inhibitors indicates that a low Ki value with thrombin is not sufficient; the inhibited complex must also form rapidly. Moreover, potent inhibition of activated protein C and plasmin could be tolerated providing the inhibited complex only forms slowly. An ideal profile of kinetic parameters with thrombin, activated protein C and plasmin is formulated and discussed in relation to various classes of thrombin inhibitors. Examination of kinetic data for thrombin inhibitors currently in clinical trials (hirudin and hirulog) indicates that they possess this ideal profile of kinetic parameters.
authors.affiliation: Department of Haematology, University of Cambridge, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Stone
authors.forename: C
authors.initials: C
authors.lastname: Tapparelli
mesh_terms: D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000991:Antithrombins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001777:Blood Coagulation / Q000187:drug effects; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011486:Protein C / Q000037:antagonists & inhibitors / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D009838:Oligodeoxyribonucleotides; D011486:Protein C; D015842:Serine Proteinase Inhibitors; D006493:Heparin; D013917:Thrombin; D005341:Fibrinolysin