Effect of tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis

被引:53
作者
Hennan, J. K. [1 ]
Morgan, G. A. [1 ]
Swillo, R. E. [1 ]
Antrilli, T. M. [1 ]
Mugford, C. [2 ]
Vlasuk, G. P. [1 ]
Gardell, S. J. [1 ]
Crandall, D. L. [1 ]
机构
[1] Wyeth Ayerst Res, Cardiovasc & Metab Dis Res, Collegeville, PA 19426 USA
[2] Wyeth Ayerst Res, Chem & Screening Sci, Collegeville, PA 19426 USA
关键词
fibrinolysis; PAI-1; thrombosis; vascular injury;
D O I
10.1111/j.1538-7836.2008.03063.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: To assess the antithrombotic and profibrinolytic effects of tiplaxtinin (PAI-039), an orally bioavailable antagonist of PAI-1, in rat models of thrombosis. Methods and results: Carotid artery and vena cava vascular injury was produced by application of FeCl3 and blood flow was monitored using ultrasonic technology. To assess efficacy in a thrombosis prevention paradigm, PAI-039 was administered orally 90 min before injury (1-30 mg kg(-1)). To assess efficacy in a thrombosis treatment paradigm, vascular injury and stable thrombus formation were followed 4 h later by recovery and PAI-039 administration. PAI-039 prevented carotid artery occlusion in 20, 68 and 60% of animals pretreated with 0.3, 1.0 and 3.0 mg kg(-1), respectively. Time to occlusive thrombosis was increased from 18.2 +/- 4.6 min in controls to 32.5 +/- 8.7 (P = ns), 46.1 +/- 7.0 (P < 0.05), and 41.6 +/- 11.3 min (P < 0.05) in the respective PAI-039 treatment groups. In the vena cava protocol, PAI-039 pretreatment significantly reduced thrombus weight at PAI-039 doses of 3, 10 and 30 mg kg(-1). When PAI-039 was dosed in a treatment paradigm 4 h after stable arterial and venous thrombosis, a significant reduction in thrombus weight was observed 24 h later at PAI-039 doses of 3, 10 and 30 mg kg(-1). PAI-039 (10, 30 and 100 mg kg(-1)) had no effect on platelet aggregation in response to ADP or collagen and was not associated with increased bleeding or prolonged prothrombin time. In animals bearing no vascular injury, PAI-039 had no effect on circulating, low-levels of PAI-1 activity. In contrast, circulating PAI-1 activity increased 5-fold following the induction of vascular injury, which was completely neutralized by PAI-039. Conclusions: PAI-039 exerts antithrombotic efficacy in rat models of arterial and venous vascular injury without effecting platelet aggregation.
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收藏
页码:1558 / 1564
页数:7
相关论文
共 22 条
[1]   THROMBOLYSIS AND REOCCLUSION IN EXPERIMENTAL JUGULAR-VEIN AND CORONARY-ARTERY THROMBOSIS - EFFECTS OF A PLASMINOGEN-ACTIVATOR INHIBITOR TYPE 1-NEUTRALIZING MONOCLONAL-ANTIBODY [J].
BIEMOND, BJ ;
LEVI, M ;
CORONEL, R ;
JANSE, MJ ;
TENCATE, JW ;
PANNEKOEK, H .
CIRCULATION, 1995, 91 (04) :1175-1181
[2]  
Charlton PA, 1996, THROMB HAEMOSTASIS, V75, P808
[3]  
COLLEN D, 1991, BLOOD, V78, P3114
[4]  
Eitzman DT, 2000, BLOOD, V96, P4212
[5]   Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: Design, synthesis, and preclinical characterization [J].
Elokdah, H ;
Abou-Gharbia, M ;
Hennan, JK ;
McFarlane, G ;
Mugford, CP ;
Krishnamurthy, G ;
Crandall, DL .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (14) :3491-3494
[6]   DETECTION AND PARTIAL CHARACTERIZATION OF AN INHIBITOR OF PLASMINOGEN-ACTIVATOR IN HUMAN-PLATELETS [J].
ERICKSON, LA ;
GINSBERG, MH ;
LOSKUTOFF, DJ .
JOURNAL OF CLINICAL INVESTIGATION, 1984, 74 (04) :1465-1472
[7]   MECHANISMS LEADING TO MYOCARDIAL-INFARCTION - INSIGHTS FROM STUDIES OF VASCULAR BIOLOGY [J].
FUSTER, V .
CIRCULATION, 1994, 90 (04) :2126-2146
[8]   Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitory [J].
Gorlatova, Natalia V. ;
Tale, Jacqueline M. ;
Elokdah, Hassan ;
Li, Donghua ;
Fan's, Kristi ;
Warnock, Mark ;
Crandall, David L. ;
Lawrence, Daniel A. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (12) :9288-9296
[9]   Evaluation of PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid], a novel plasminogen activator inhibitor-1 inhibitor, in a canine model of coronary artery thrombosis [J].
Hennan, JK ;
Elokdah, H ;
Leal, M ;
Ji, A ;
Friedrichs, GS ;
Morgan, GA ;
Swillo, RE ;
Antrilli, TM ;
Hreha, A ;
Crandall, DL .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 314 (02) :710-716
[10]   Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice [J].
Konstantinides, S ;
Schäfer, K ;
Thinnes, T ;
Loskutoff, DJ .
CIRCULATION, 2001, 103 (04) :576-583