Factor VIIa inhibitors: Chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model
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- 作者：Wendy B. Young ; Joyce Mordenti ; Steven Torkelson ; William D. Shrader ; Aleksandr Kolesnikov ; Roopa Rai ; Liang Liu ; Huiyong Hu ; Ellen M. Leahy ; Michael J. Green et al.
- 关键词：Factor VIIa ; fVIIa ; Tissue factor ; TF ; Coagulation ; Antithrombotic ; Baboon thrombosis model ; Pharmacokinetics ; Pharmacodynamics ; Serine protease ; Thrombin ; Factor Xa
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2006
- 出版时间：1 April 2006
- 年：2006
- 卷：16
- 期：7
- 页码：2037-2041
- 全文大小：256 K
文摘
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.