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Thromb Haemost 1996; 75(05): 808-815
DOI: 10.1055/s-0038-1650371
Original Article
Schattauer GmbH Stuttgart

Evaluation of a Low Molecular Weight Modulator of Human Plasminogen Activator Inhibitor-1 Activity

Peter A Charlton
1   Xenova Limited, Slough, Berkshire, UK
,
Richard W Faint
1   Xenova Limited, Slough, Berkshire, UK
,
Fiona Bent
1   Xenova Limited, Slough, Berkshire, UK
,
Justin Bryans
1   Xenova Limited, Slough, Berkshire, UK
,
Inês Chicarelli-Robinson
1   Xenova Limited, Slough, Berkshire, UK
,
Ian Mackie
2   The Haematology Department, University College London, UK
,
Samuel Machin
2   The Haematology Department, University College London, UK
,
Paul Bevan
1   Xenova Limited, Slough, Berkshire, UK
› Author Affiliations
Further Information

Publication History

Received 28 August 1995

Accepted after resubmission 08 February 1996

Publication Date:
26 July 2018 (online)

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Summary

A critical component in the regulation of thrombus formation and clearance is the balance between tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAM). An increase in the plasma concentration of PAH has been proposed as a risk factor in thrombotic disease. Inhibition of PAI-1 activity may have utility in the treatment of thromboembolic disease. We report here the evaluation of three diketopiperazine-based low molecular weight inhibitors of PAI-1 activity (XR334, XR1853 and XR5082). In vitro these compounds reversed the inhibitory effects of PAI-1 against both tPA and urokinase (UK) (IC50:5 to 80 μM). In contrast, other serpin-serine protease interactions, including α1-antitrypsin-trypsin, α2-antiplasmin-plasmin and antithrombin-thrombin, were not affected, neither did these inhibitors affect global tests of haemostasis. In the light of this promising in vitro profile these compounds were evaluated in a standard radioisotopic assay of clot lysis in whole rat blood following intravenous administration. In this assay these compounds dose-dependently enhanced fibrinolysis ex vivo. After intravenous bolus administration XR334, XR1853 and XR5082 at 5 mg/kg increased clot lysis by 32.0 ± 5.1% SEM (n = 25, p <0.01), 36.7 ± 3.5% SEM (n = 36, p <0.01) and 60.0 ± 2.8% SEM (n = 17, p <0.01) respectively compared to vehicle. Intravenous infusion of these compounds (1 mg/kg/min for 20 min) significantly prolonged (approximately twofold) the time to blood vessel occlusion in the rat electrically-stimulated carotid artery thrombosis model. Thus, these low molecular weight inhibitors of PAI-1 activity enhanced fibrinolysis ex vivo and protected against thrombus formation in the rat.

 

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