Abstract
The synthesis and evaluation of inhibitors of activated protein C (aPC) are reported. This serine protease is partly responsible for the degradation of factor VIIIa, involved in the regulation of bleeding in hemophilia A. Benzamidine-containing derivatives were found to be potent aPC inhibitors, some of them showing selectivity against the procoagulant protease thrombin. Moreover, compound 1 significantly restored the generation of thrombin in hemophiliac plasma.
MeSH terms
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Benzamidines / chemistry
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Benzamidines / pharmacology*
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Factor VIIIa / metabolism
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Hemophilia A / drug therapy*
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Hemorrhage / prevention & control*
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Humans
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Molecular Structure
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Molecular Weight
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Protein C / antagonists & inhibitors*
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors
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Thrombin / biosynthesis
Substances
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Benzamidines
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Protein C
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Serine Proteinase Inhibitors
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Factor VIIIa
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Thrombin