NOVEL LOW-MOLECULAR-WEIGHT INHIBITOR OF PAI-1 (XR5118) PROMOTES ENDOGENOUS FIBRINOLYSIS AND REDUCES POSTTHROMBOLYSIS THROMBUS GROWTH IN RABBITS

FRIEDERICH PW LEVI M BIEMOND BJ CHARLTON P TEMPLETON D VANZONNEVELD AJ BEVAN P PANNEKOEK H TENCATE JW

Pw. Friederich et al., NOVEL LOW-MOLECULAR-WEIGHT INHIBITOR OF PAI-1 (XR5118) PROMOTES ENDOGENOUS FIBRINOLYSIS AND REDUCES POSTTHROMBOLYSIS THROMBUS GROWTH IN RABBITS, Circulation, 96(3), 1997, pp. 916-921

28

INGLESE

Article

Peripheal Vascular Diseas",Hematology

Circulation → ACNP

0009-7322

96

3

1997

916 - 921

ISI

0009-7322(1997)96:3<916:NLIOP(>2.0.ZU;2-T

Background Elevated levels of plasminogen activator inhibitor 1 (PAI-I ) have been associated with the occurrence of thrombotic disease, and inhibition of PAI-I activity in vivo resulted in enhanced thrombolysis and a reduction in reocclusion. Besides monoclonal antibodies and pep tides, no suitable agents that are able to block PAI-1 activity are av ailable to date. The present study was designed to test the interactio n between a nonantibody, nonpeptide, diketopiperazine-based inhibitor of PAI-1, XR5118, and PAI-1 and to assess the effect of XR5118 on PAI- 1 activity in vitro and on in vivo thrombolysis and thrombus growth in an experimental thrombosis model in rabbits. Methods and Results The binding site of XR5118 on the PAI-1 molecule was studied by competitiv e binding experiments with mapped anti-PAI-l monoclonal antibodies by use of surface plasmon resonance experiments. XR5118 selectively and c ompetitively inhibited binding of the PAI-l-inhibiting monoclonal anti body CLB-2C8, indicating that binding of XR5118 to PAI-1 takes place a t the area between amino acids 110 and 145 of the PAI-I molecule, whic h is known to be involved with the binding of PAI-1 to tissue plasmino gen activator (TPA). Incubation of plasma or platelet releasate with X R5118 resulted in a dose-dependent inhibition of PAI-I activity. Syste mic infusion of XR5118 induced a significant reduction in plasma PAI-1 activity levels from 23.7+/-4.9 to 10.9+/-3.4 IU/mL. Administration o f XR5118 resulted in a significant, twofold increase in endogenous thr ombolysis compared with the control. Thrombus growth in rabbits receiv ing both XR5118 and rTPA was significantly attenuated compared with ra bbits receiving rTPA alone (13.5+/-2.7% versus 19.9+/-3.88, respective ly). Conclusions XR5118 binds to PAI-1 and reduces plasma PAI-1 activi ty levels. Furthermore, XR5118 promotes endogenous thrombolysis and in hibits thrombus accretion and is the first nonpeptide compound with si gnificant anti-PAI-l activity in vivo in these models.