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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 28, 2005; DOI: 10.1124/jpet.105.084129

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Received for publication January 25, 2005.
Revised April 26, 2005.
Accepted for publication April 26, 2005.

Evaluation of PAI-039, a Novel PAI-1 Inhibitor, in a Canine Model of Coronary Artery Thrombosis

James K Hennan 1*, Hassan Elokdah 1, Mauricio Leal 1, Allena Ji 1, Gregory S. Friedrichs 1, Gwen A. Morgan 1, Robert E. Swillo 1, Thomas M. Antrilli 1, Amy Hreha 1, David L. Crandall 1

1 Wyeth Research

* Address correspondence to: E-mail: hennanj{at}wyeth.com

Abstract

Background: We tested a novel, orally active inhibitor of plasminogen activator inhibitor-1 (PAI-1) in a canine model of electrolytic injury. Methods and Results: Dogs received by oral gavage either vehicle (control) or the PAI-1 inhibitor PAI-039 (1, 3, and 10mg/kg) and were subjected to electrolytic injury of the coronary artery. PAI-039 caused prolongation in time to coronary occlusion (control 31.7±6.3min, PAI-039 3mg/kg 66.0±6.4min, 10mg/kg 56.7±7.4min, n=5-6, p<0.05) and a reduced thrombus weight (control 7.6±1.5mg, PAI-039 10mg/kg 3.6±1.0mg, p<0.05). While occlusive thrombosis was observed across all groups based upon absence of measurable blood flow, a high incidence (>60%) of spontaneous reperfusion occurred only in those groups receiving PAI-039. Spontaneous reperfusion in the 10 mg/kg PAI-039 group accounted for total blood flow (area under the curve of coronary blood flow) of 99.6±11.7 ml after initial thrombotic occlusion (p<0.05 compared to control). Plasma PAI-1 activity was reduced in all drug-treated groups (percent reduction in activity p<0.05, 10 mg/kg PAI-039), while ADP-, U46619-, and collagen-induced platelet aggregation, as well as template bleeding and prothrombin time, remained unaffected by PAI-039. Ex vivo clot lysis analysis revealed normal clot formation, but accelerated clot lysis in PAI-039 treated groups. The pharmacokinetic profile of PAI-039 indicated an oral bioavailability of 43±15.3% and a plasma half-life of 6.2±1.3 hr. Conclusions: PAI-039 is an orally active prothrombolytic drug that inhibits PAI-1 and accelerates fibrinolysis while maintaining normal coagulation in a model of coronary occlusion.


Key words: Artery, Electrolytic injury, Fibrinolysis, PAI-1, Thrombosis, Tissue plasminogen activator


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