Abstract
Summary 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 IC50 value of 3.5 μM±0.19 μM (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 (1–5mg/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
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