Nonbenzamidine isoxazoline derivatives as factor Xa inhibitors

Factor Xa (fXa) is an important serine protease in the blood coagulation cascade. Inhibition of fXa has emerged as an attractive target for potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein, we describe a series of non-benzamidine isoxazoline derivat...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2003-03, Vol.13 (6), p.1023-1028
Main Authors: Quan, Mimi L., Ellis, Christopher D., He, Ming Y., Liauw, Ann Y., Lam, Patrick Y.S., Rossi, Karen A., Knabb, Robert M., Luettgen, Joseph M., Wright, Matthew R., Wong, Pancras C., Wexler, Ruth R.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biological Availability
Blood. Blood coagulation. Reticuloendothelial system
Chromatography, High Pressure Liquid
Dogs
Factor Xa Inhibitors
Fibrinolytic Agents - chemical synthesis
Fibrinolytic Agents - pharmacokinetics
Fibrinolytic Agents - pharmacology
Half-Life
Humans
In Vitro Techniques
Indicators and Reagents
Isoxazoles - chemical synthesis
Isoxazoles - pharmacokinetics
Isoxazoles - pharmacology
Kinetics
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Rabbits
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Summary:Factor Xa (fXa) is an important serine protease in the blood coagulation cascade. Inhibition of fXa has emerged as an attractive target for potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein, we describe a series of non-benzamidine isoxazoline derivatives as fXa inhibitors. The chloroaniline group was found to be the most potent benzamidine mimic in this series. Chloroaniline 1 (ST368) has a K i value of 1.5 nM against fXa and is highly selective for fXa relative to thrombin and trypsin. A series of nonbenzamidine isoxazoline fXa inhibitors is described. The chloroaniline group was found to be the most potent benzamidine mimic in this series. Chloroaniline 1 (ST368) has a K i value of 1.2 nM against fXa and is highly selective for fXa relative to thrombin and trypsin.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(03)00080-5