Summary
Current clinical use of heparin as an antithrombotic agent is limited by suboptimal
efficacy and safety considerations. Thrombin’s central role in thrombosis makes it
an attractive target to develop more effective and safer antithrombotic agents. BCH-2763
is a novel, potent (Ki: 0.11 nM), low molecular weight (1.51 kDa), bivalent direct
thrombin inhibitor. The antithrombotic efficacy of BCH-2763 in vivo following i.v. bolus plus infusion in rats was compared in arterial and venous thrombosis
models with two other bivalent direct thrombin inhibitors, r-hirudin and hirulog,
with two catalytic site-directed thrombin inhibitors, inogatran and argatroban, and
with heparin. In vivo efficacy was related to inhibition in vitro of fibrin clot formation, thrombin-induced aggregation of rat or human washed platelets
and activity of free and plasma clot-bound thrombin. All the direct thrombin inhibitors
were effective on both arterial and venous thrombosis at markedly lower fold aPTT
increases than heparin. The antithrombotic doses of all inhibitors against venous
thrombosis were less than against arterial thrombosis. The rank order of potency based
on doses (mg/kg/h) required for full efficacy against arterial thrombosis was BCH-2763
(1.2) inogatran (1.5) r-hirudin (1.8) hirulog (3.3) argatroban ( 3.0); heparin required
a markedly higher dose (5.7). In venous thrombosis the doses required for full efficacy
were substantially lower for the bivalent (BCH-2763: 0.12; r-hirudin: 0.12; hirulog:
0.18) than for the catalytic site-directed (inogatran: 0.48; argatroban: 0.90) thrombin
inhibitors; the dose required for heparin was 0.19. All the direct thrombin inhibitors
caused similar shifts in aPTT at doses required to inhibit arterial thrombosis, but
BCH-2763 inhibited venous thrombosis at lower aPTT fold increases. In vivo antithrombotic efficacy of direct thrombin inhibitors correlated with their inhibitory
activity in vitro against fibrin clot formation and platelet aggregation. In contrast to heparin, all
the direct thrombin inhibitors inhibited plasma clot-bound thrombin, but the relative
IC50 s did not correlate with their antithrombotic efficacy. In summary, direct thrombin
inhibitors are more effective than heparin in inhibiting arterial and venous thrombosis
in rats with less aPTT increases. BCH-2763 is effective at lower doses than the other
direct thrombin inhibitors and for venous thrombosis at a smaller aPTT increase. BCH-2763
may offer an improved therapeutic index in the treatment of thromboembolic complications
over heparin and other direct thrombin inhibitors.
