UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity

Charlton, PA; Faint, RW; Bent, F; Bryans, J; ChicarelliRobinson, I; Mackie, I; Machin, S; (1996) Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity. THROMB HAEMOSTASIS , 75 (5) 808 - 815.

Full text not available from this repository.

Abstract

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 (PAI-1). An increase in the plasma concentration of 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. We report here the evaluation of three diketopiperazine-based low molecular weight inhibitors of PAI-I 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 mu M). In contrast, other serpin-serine protease interactions, including alpha(1)-antitrypsin-trypsin, alpha(2)-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-I activity enhanced fibrinolysis ex vivo and protected against thrombus formation in the rat.

Type: Article
Title: Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity
Keywords: ACUTE MYOCARDIAL-INFARCTION, T-PA ACTIVITY, RISK FACTOR, VENOUS THROMBOSIS, CLOT LYSIS, TYPE-1, PAI-1, PLASMA, FIBRINOLYSIS, THROMBOLYSIS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1324259
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item