In Vitro and In Vivo Antithrombotic Activity of PD-198961, a Novel Synthetic Factor Xa Inhibitor
Liguo Chi, Yun-Wen Peng, Glenn Gibson, Gary Hicks, Thomas E Mertz, Stephen Rapundalo, Nancy Janiczek, Jeremy J Edmunds, Robert Leadley
Journal of Cardiovascular Pharmacology
PD-198961, 3-(4-5-[(2R,6S )-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-4hydroxybenzenecarboximidamide, is a novel, synthetic factor Xa inhibitor with a Ki of 2.7 nM against human factor Xa. The aim of the present study was to evaluate the pharmacokinetic profile and antithrombotic efficacy of PD-198961 in rabbits. When tested in vitro, PD-198961 doubled prothrombin time (PT) and activated partial thromboplastin time (aPTT) at concentrations of 0.13 and 0.32
... M in human plasma, 0.2 and 0.09 µM in rabbit plasma, 0.3 and 0.4 µM in dog plasma, respectively. Intravenous administration of PD-198961 at 1 mg/kg over 30 minutes resulted in a maximal prolongation in PT and aPTT of 4.9 ± 0.4 and 4.1 ± 0.9-fold of baseline, respectively. The peak plasma concentration of PD-198961 was 977 ± 96 ng/ml. The anticoagulant effect of PD-198961 was readily reversible; coagulation parameters and plasma concentration returned to near baseline 15 minutes after cessation of infusion. There was a good correlation between PT prolongation and plasma concentration of PD-198961 (r = 0.93). In an FeCl 3 -induced model of arterial thrombosis in rabbits, the antithrombotic effects of PD-198961 were compared with that of LB-30057, a direct thrombin inhibitor, and enoxaparin, a low molecular weight heparin (LMWH). PD-198961 dose dependently increased the time to occlusion (TTO), reduced thrombus weight (TW), and decreased the incidence of occlusion. When administered at 3.0 µg/kg/min IV, PD-198961 prolonged TTO from 28 ± 5 minutes (control) to 120 ± 0 minutes (P < 0.001) and reduced TW from 9.9 ± 1.5 mg (control) to 2.8 ± 0.9 mg (P < 0.01). PD-198961 also dose dependently inhibited ex vivo plasma FXa activity. At the highest dose tested, PD-198961 increased aPTT to 1.4 ± 0.1-fold of baseline (compared with 1.5 ± 0.1 and 2.8 ± 0.3-fold of baseline for LB-30057 [CI-1028] and enoxaparin, respectively), and had modest effects on bleeding time (Յ 2-fold). These results indicate that PD-198961 is a potent FXa inhibitor and an effective antithrombotic agent at doses that produce only modest changes in normal hemostasis. P < 0.05, b P < 0.01, Fisher's Exact Test. TW, thrombus weight; TTO, time to occlusion. FIGURE 3. The correlation analysis between each coagulation parameter (aPTT, TT, ACT, PT) and plasma PD-198961 concentration. The data were obtained from the same group of rabbits used to generate the data presented in Figure 2 .