XR5118, a novel modulator of plasminogen activator inhibitor-1 (PAI-1), increases endogenous tPA activity in the rat

XR5118, a diketopiperazine-based low molecular weight inhibitor of plasminogen activator inhibitor-1 (PAI-1) activity, was studied ex vivo and in vivo in the rat to determine whether inhibition of PAI-1 activity resulted in increased fibrinolysis and protection against thrombus formation. XR5118 reversed the inhibitory effects of human PAI-1 against tissue-type plasminogen activator (tPA), in an vitro amidolytic assay (S2251) with an IC(50) value of 3.5 mu M+/-0.19 mu M (n=7). This activity was confirmed in in vitro fibrinolysis assays against both human and rat PAI-1 and, following intravenous administration to rats, XR5118 (1-5 mg/kg) dose-dependently increased clot lysis in an ex vivo dilute blood clot lysis time (DBCLT) assay. At 5 mg/kg, XR5118 increased clot lysis by 41+/-1.6% (n=39, P<0.01) relative to vehicle control. In a rat model of arterial thrombosis, intravenous infusion of XR5118 (0.5 mg/kg/min for 20 min) significantly prolonged the time to thrombus formation from 21.2+/-2.5 min in the vehicle-treated group to 37.0+/-5.4 min (n=10 per group, P<0.01). Furthermore, infusion of XR5118 was associated with a significant decrease in plasma PAI-1 activity and a significant increase in plasma tPA activity. Thus, in the rat, XR5118 enhanced fibrinolysis ex vivo, increased endogenous tPA activity, and attenuated arterial thrombus formation following electrical injury. As elevated PAI-1 has been proposed as a risk factor in thrombotic disease, inhibition of PAI-1 activity may have utility in the treatment of thromboembolic disease.