title: Antithrombotic properties of RWJ-50353, a potent and novel thrombin inhibitor.
abstract: The antithrombotic, anticoagulant, and kinetic properties of RWJ-50353, a novel, reversible, active-site-directed thrombin inhibitor, were evaluated. RWJ-50353 inhibited the catalytic activity of human alpha-thrombin with a K(i) of 0.19+/-0.02 nM. It showed a 16-fold selectivity relative to inhibition of trypsin and at least 330-fold selectivity relative to inhibition of other biologically important serine proteases. In a gel-filtered platelet preparation, RWJ-50353 inhibited alpha-thrombin-induced aggregation with an IC(50) of 32+/-6 nM. In a canine arteriovenous shunt antithrombotic model, RWJ-50353 demonstrated a significant dose-related (0.1-1.0 mg/kg, i.v.) reduction in thrombus formation with 50% inhibition (ID(50)) obtained at 0.46+/-0.1 mg/kg. In a rabbit deep vein thrombosis model, RWJ-50353 dose-dependently (0.1-1. 0 mg/kg, i.v.) reduced thrombus formation with an ID(50) of 0.25+/-0. 03 mg/kg. The antithrombotic activity in both of these models was associated with only mild prolongations in bleeding time and coagulation parameters. These results demonstrate that RWJ-50353 is a potent, selective thrombin inhibitor that is an effective antithrombotic agent after intravenous administration in models of arterial and venous thrombosis and may be useful in the management of various thrombotic disorders.
authors.affiliation: R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Giardino
authors.forename: M J
authors.initials: MJ
authors.lastname: Costanzo
authors.forename: J A
authors.initials: JA
authors.lastname: Kauffman
authors.forename: Q S
authors.initials: QS
authors.lastname: Li
authors.forename: B E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: P
authors.initials: P
authors.lastname: Andrade-Gordon
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D013844:Thiazoles / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D005343:Fibrinolytic Agents; D006146:Guanidines; D006490:Hemostatics; D010975:Platelet Aggregation Inhibitors; C100912:RWJ 50353; D013844:Thiazoles; D013917:Thrombin