WAY-140312 reduces plasma PAI-1 while maintaining normal platelet aggregation.
Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of tissue plasminogen activator (tPA) and is elevated in diseases of vascular remodeling. In this study, we describe an inhibitor of active PAI-1, WAY-140312. Using fluorescence spectroscopy, it was determined that WAY-140312 bound PAI-1 at a single binding site with a dissociation constant of 5 microM. In a biochemical assay determining direct tPA activity, human recombinant PAI-1 completely inhibited tPA, but this inhibition was blocked by WAY-140312 at an IC(50) of 15.6 microM. In vivo, a 10 mg/kg oral dose of WAY-140312 to rats produced a significant plasma reduction of active PAI-1. Bleeding time, thrombin clotting time, and ex vivo platelet aggregation induced by ADP (20 microM) or collagen (2.5 microg/ml) were not affected by administration of WAY-140312. These results are the first to demonstrate that an orally active PAI-1 inhibitor can reduce plasma PAI-1 activity while maintaining normal platelet aggregation and coagulation.
Crandall
David L
DL
Cardiovascular and Metabolic Diseases Research, Wyeth Research, Collegeville, PA 19426, USA. CrandaD@Wyeth.com
Hennan
James K
JK
Elokdah
Hassan
H
Krishnamurthy
Girija
G
Antrilli
Thomas M
TM
Bauer
Jean S
JS
Morgan
Gwen A
GA
Swillo
Robert E
RE
D000284:Administration, Oral; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006470:Hemorrhage / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D017395:Plasminogen Activator Inhibitor 1