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 pla sminogen activator inhibitor-1 (PAI-1) activity, was studied ex vivo a nd in vivo in the rat to determine whether inhibition of PAI-1 activit y resulted in increased fibrinolysis and protection against thrombus f ormation. XR5118 reversed the inhibitory effects of human PAI-1 agains t tissue-type plasminogen activator (tPA), in an vitro amidolytic assa y (S2251) with an IC50 value of 3.5 mu M+/-0.19 mu M (n=7). This activ ity was confirmed in in vitro fibrinolysis assays against both human a nd rat PAI-1 and, following intravenous administration to rats, XR5118 (1-5 mg/kg) dose-dependently increased clot lysis in an ex vivo dilut e blood clot lysis time (DBCLT) assay. At 5 mg/kg, XR5118 increased cl ot 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 fo rmation 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 ass ociated with a significant decrease in plasma PAI-1 activity and a sig nificant increase in plasma tPA activity. Thus, in the rat, XR5118 enh anced fibrinolysis ex vivo, increased endogenous tPA activity, and att enuated arterial thrombus formation following electrical injury. As el evated PAI-1 has been proposed as a risk factor in thrombotic disease, inhibition of PAI-1 activity may have utility in the treatment of thr omboembolic disease.