Title of article :
Factor VIIa inhibitors: Chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model
Author/Authors :
Wendy B. Young، نويسنده , , Joyce Mordenti، نويسنده , , Steven Torkelson، نويسنده , , William D. Shrader، نويسنده , , Aleksandr Kolesnikov، نويسنده , , Roopa Rai، نويسنده , , Liang Liu، نويسنده , , Huiyong Hu، نويسنده , , Ellen M. Leahy، نويسنده , , Michael J. Green، نويسنده , , Paul A. Sprengeler، نويسنده , , Mary E. McGrath and Bradley A. Katz، نويسنده , , Christine Yu، نويسنده , , James W. Janc، نويسنده , , Kyle C. Elrod، نويسنده , , Ulla M. Marzec، نويسنده , , Stephen R. Hanson، نويسنده ,
Abstract :
Highly selective and potent factor VIIa–tissue factor (fVIIa • TF) complex inhibitors were generated through structure-based design. The pharmacokinetic properties of an optimized analog (9) were characterized in several preclinical species, demonstrating pharmacokinetic characteristics suitable for once-a-day dosing in humans. Analog 9 inhibited platelet and fibrin deposition in a dose-dependent manner after intravenous administration in a baboon thrombosis model, and a pharmacodynamic concentration–response model was developed to describe the platelet deposition data. Results for heparin and enoxaparin (Lovenox®) in the baboon model are also presented.
Keywords :
Baboon thrombosis model , Pharmacokinetics , Pharmacodynamics , Serine protease , thrombin , factor Xa , Factor VIIa , FVIIa , tissue factor , coagulation , antithrombotic , TF
