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.
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-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (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.
Hennan
James K
JK
Cardiovascular and Metabolic Disease, Wyeth Research, N2252A, P.O. Box 42528, Philadelphia, PA 19101, USA. hennanj@wyeth.com
Elokdah
Hassan
H
Leal
Mauricio
M
Ji
Allena
A
Friedrichs
Gregory S
GS
Morgan
Gwen A
GA
Swillo
Robert E
RE
Antrilli
Thomas M
TM
Hreha
Amy
A
Crandall
David L
DL
D000085:Acetates / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001760:Bleeding Time; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D023381:Endpoint Determination; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects; D007210:Indoleacetic Acids; D007211:Indoles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D010314:Partial Thromboplastin Time; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D000085:Acetates; D005343:Fibrinolytic Agents; D007210:Indoleacetic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin