Novel low-molecular-weight inhibitor of PAI-1 (XR5118) promotes endogenous fibrinolysis and reduces postthrombolysis thrombus growth in rabbits.

Elevated levels of plasminogen activator inhibitor 1 (PAI-1) have been associated with the occurrence of thrombotic disease, and inhibition of PAI-1 activity in vivo resulted in enhanced thrombolysis and a reduction in reocclusion. Besides monoclonal antibodies and peptides, no suitable agents that are able to block PAI-1 activity are available to date. The present study was designed to test the interaction 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.
The binding site of XR5118 on the PAI-1 molecule was studied by competitive binding experiments with mapped anti-PAI-1 monoclonal antibodies by use of surface plasmon resonance experiments. XR5118 selectively and competitively inhibited binding of the PAl-1-inhibiting monoclonal antibody CLB-2C8, indicating that binding of XR5118 to PAI-1 takes place at the area between amino acids 110 and 145 of the PAI-1 molecule, which is known to be involved with the binding of PAI-1 to tissue plasminogen activator (TPA). Incubation of plasma or platelet releasate with XR5118 resulted in a dose-dependent inhibition of PAI-1 activity. Systemic 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 of XR5118 resulted in a significant, twofold increase in endogenous thrombolysis compared with the control. Thrombus growth in rabbits receiving both XR5118 and rTPA was significantly attenuated compared with rabbits receiving rTPA alone (13.5+/-2.7% versus 19.9+/-3.8%, respectively).
XR5118 binds to PAI-1 and reduces plasma PAI-1 activity levels. Furthermore, XR5118 promotes endogenous thrombolysis and inhibits thrombus accretion and is the first nonpeptide compound with significant anti-PAI-1 activity in vivo in these models.
AuthorsP W Friederich, M Levi, B J Biemond, P Charlton, D Templeton, A J van Zonneveld, P Bevan, H Pannekoek, J W ten Cate
JournalCirculation (Circulation) Vol. 96 Issue 3 Pg. 916-21 (Aug 5 1997) ISSN: 0009-7322 [Print] UNITED STATES
PMID9264501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Piperazines
  • Plasminogen Activator Inhibitor 1
  • XR 5118
  • Thrombin
  • Animals
  • Blood Platelets (metabolism)
  • Fibrinolysis (drug effects)
  • Humans
  • Jugular Veins
  • Molecular Weight
  • Piperazines (chemistry, metabolism, pharmacology)
  • Plasma (metabolism)
  • Plasminogen Activator Inhibitor 1 (blood, metabolism)
  • Rabbits
  • Thrombin (pharmacology)
  • Thrombophlebitis (blood, prevention & control)

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