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CARDIOVASCULAR

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

Cardiovascular and Metabolic Disease Research (J.K.H., G.S.F., G.A.M., R.E.S., T.M.A., A.H., D.L.C.), Chemical and Screening Sciences (H.E.), and Bioanalytical R&D (M.L., A.J.), Wyeth Research, Collegeville, Pennsylvania

We tested a novel, orally active inhibitor of plasminogen activator inhibitor-1 (PAI-1) in a canine model of electrolytic injury. Dogs received by oral gavage either vehicle (control) or the PAI-1 inhibitor PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid] (1, 3, and 10 mg/kg) and were subjected to electrolytic injury of the coronary artery. PAI-039 caused prolongation in time to coronary occlusion (control, 31.7 ± 6.3 min; 3 mg/kg PAI-039, 66.0 ± 6.4 min; 10 mg/kg, 56.7 ± 7.4 min; n = 5–6; p < 0.05) and a reduced thrombus weight (control, 7.6 ± 1.5 mg; 10 mg/kg PAI-039, 3.6 ± 1.0 mg; p < 0.05). Although occlusive thrombosis was observed across all groups based upon the 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 with control). Plasma PAI-1 activity was reduced in all drug-treated groups (percentage of reduction in activity p < 0.05; 10 mg/kg PAI-039), whereas ADP-, 9,11-dideoxy-11,9-epoxymethanoprostaglandin F₂ (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 h. In conclusion, 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.

Address correspondence to: Dr. James K. Hennan, Wyeth Research, N2252A, P.O. Box 42528, Philadelphia, PA 19101. E-mail: hennanj{at}wyeth.com

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