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Abstract
Author(s) -
Qingyun Wu,
Katherine K. Tran,
Amy Liang,
Feng Wu,
Baoying Ye,
YuZhong Wang,
Ronald Vergona,
John Morser,
Daniel T. Eitzman,
Zhihui Zhao,
Jeffrey I. Weitz,
Petr Klement,
Peng Liao,
Alan R. Stafford,
James C. Fredenburgh,
Klaus Johansen,
Jack Hirsh,
Mortimer Poncz,
Dubravka Kufrin,
Don Eslin,
Khalil Bdeir,
Juan-Carlos Murciano,
Alice Kuo,
Jay L. Degen,
Brue S. Sachais,
Douglas B. Cines,
W. E. Meehan,
G Knitter,
Gerry Lasser,
Kevin M. Lewis,
Paul D. Bishop,
Ulla M. Marzec,
Stephen C. Hanson,
Joachim Fruebis
Publication year - 2003
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2003.tb00142.x
Subject(s) - thursday , citation , library science , computer science , philosophy , linguistics
OC358 Development of small molecule compounds that inhibit PAI1 activity in vitro and in vivo Hall 1 15:00 17th July, 2003 Session Type: Oral communications Subject area: New antithrombotic agents and approaches Session title: New antithrombotics II Abstract: OC358 Authors: Q. Wu*, K. Tran*, A. Liang*, F. Wu*, B. Ye*, Y.X. Wang, R. Vergona*, J. Morser*, D. Eitzman+ & Z. Zhao* *Berlex Biosciences, USA; +U. Michigan Medical Center, USA Plasminogen activator inhibitor (PAI-1) is a major negative regulator of tissue plasmianogen activator (tPA) and urokinase (uPA). High levels of PAI-1 antigen are associated with thrombotic diseases. In animal models, inhibition of PAI-1 activity prevents arterial and venous thrombosis. Thus, PAI-1 inhibitors may represent a new class of antithrombotics with a mechanism distinct from antiplatelet or anticoagulant agents. To develop small molecule PAI-1 inhibitors, we screened compound libraries using a chromogenic substrate-based uPA/PAI-1 assay and identified a class of menthol-substituted compounds that inhibited human PAI-1 activity. The compounds were optimized by combinatorial and medicinal chemistry to improve their potency and pharmacokinetic properties. A lead compound from this series inhibited PAI-1 activity in the uPA/PAI-1 and a tPA-mediated fibrin clot lysis assays with IC50 values of 300 and 10 nM, respectively. In a BIAcore-based assay, this series of compounds were shown to bind directly to PAI-1, but not tPA, and prevent the binding of PAI-1 to tPA in a dose-dependent manner. The compounds did not cause conversion of active PAI-1 to latent PAI-1. When administered intravenously in rats, the lead compound inhibited (IC50: 2.5 μM) the activity of plasma PAI-1 induced by LPS injection but had no significant effect on PAI-1 antigen levels. In a mouse model of thrombosis induced by photochemical injury, the lead compound (10 mg kg-1, i.v.) prolonged the time to occlusion in carotid artery as compared to vehicle controls (62.5 ± 21.1 vs. 36.4 ± 10.1 min, n = 8, P < 0.01). These results demonstrate the feasibility of developing small molecule PAI-1 inhibitors as new therapeutic agents to prevent thrombosis. file:////ddn-453/d/ML3G-Data/JTH-Abstract-2003/HTML/Thursday/Abstract%20OC358.html [1/27/2014 4:29:36 PM]