Vol. 303, Issue 3, 1189-1198, December 2002

SSR182289A, a Novel, Orally Active Thrombin Inhibitor: In Vitro Profile and ex Vivo Anticoagulant Activity

Christopher N. Berry, Gilbert Lassalle, Catherine Lunven , Jean-Michel Altenburger, Frédérique Guilbert, Alain Lalé, Jean-Pascal Hérault, Catherine Lecoffre, Christian Pfersdorff, Jean-Marc Herbert and Stephen E. O'Connor

Sanofi-Synthélabo Research, Cardiovascular-Thrombosis Department, Chilly-Mazarin and Toulouse, France (C.N.B., G.L., C.L., J.-M.A., F.G., A.L., J.-P.H., C.L., J.-M.H., S.E.O.); and Safety Department, Sanofi-Synthélabo, Montpellier, France (C.P.)

SSR182289A competitively inhibits human thrombin (K_i = 0.031 ± 0.002 µM) and shows good selectivity with respect to other human proteases, e.g., trypsin (K_i = 54 ± 2 µM), factor Xa (K_i = 167 ± 9 µM), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K_i values >250 µM). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC₁₀₀ thrombin time 96 ± 7 nM) and inhibited tissue factor-induced thrombin generation (IC₅₀ of 0.15 ± 0.02 µM). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC₅₀ value of 32 ± 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 ± 356%; ecarin clotting time (ECT), 1134 ± 204%; and activated partial thromboplastin time (aPTT), 91 ± 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 ± 425%; ECT, 2017 ± 341%; and aPTT, 113 ± 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.