TY - JOUR T1 - Evaluation of PAI-039 [{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1<em>H</em>-indol-3-yl}(oxo)acetic Acid], a Novel Plasminogen Activator Inhibitor-1 Inhibitor, in a Canine Model of Coronary Artery Thrombosis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 710 LP - 716 DO - 10.1124/jpet.105.084129 VL - 314 IS - 2 AU - James K. Hennan AU - Hassan Elokdah AU - Mauricio Leal AU - Allena Ji AU - Gregory S. Friedrichs AU - Gwen A. Morgan AU - Robert E. Swillo AU - Thomas M. Antrilli AU - Amy Hreha AU - David L. Crandall Y1 - 2005/08/01 UR - http://jpet.aspetjournals.org/content/314/2/710.abstract N2 - 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 &lt; 0.05) and a reduced thrombus weight (control, 7.6 ± 1.5 mg; 10 mg/kg PAI-039, 3.6 ± 1.0 mg; p &lt; 0.05). Although occlusive thrombosis was observed across all groups based upon the absence of measurable blood flow, a high incidence (&gt;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 &lt; 0.05 compared with control). Plasma PAI-1 activity was reduced in all drug-treated groups (percentage of reduction in activity p &lt; 0.05; 10 mg/kg PAI-039), whereas ADP-, 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α (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. The American Society for Pharmacology and Experimental Therapeutics ER -