Abstract
Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over thrombin and trypsin.
MeSH terms
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Animals
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Biological Availability
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Dogs
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Factor Xa Inhibitors*
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Humans
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In Vitro Techniques
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Kinetics
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Models, Molecular
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Molecular Mimicry
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Protein Conformation
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Rabbits
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacokinetics
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Tetrazoles / chemical synthesis*
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Tetrazoles / pharmacokinetics
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Tetrazoles / pharmacology*
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Thrombin / antagonists & inhibitors
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Trypsin Inhibitors / pharmacology
Substances
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Factor Xa Inhibitors
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Serine Proteinase Inhibitors
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Tetrazoles
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Trypsin Inhibitors
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Thrombin