Abstract
Thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator of fibrinolysis, and inhibitors of this enzyme have potential use in antithrombotic and thrombolytic therapy. Appropriately substituted imidazole acetic acids such as 10j were found to be potent inhibitors of activated TAFI and selective versus the related carboxypeptidases CPA, CPN, and CPM but not CPB. Further, 10j accelerated clot lysis in vitro and was shown to be efficacious in a primate model of thrombosis.
MeSH terms
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Acetates / chemical synthesis*
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Acetates / pharmacokinetics
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Acetates / pharmacology
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Aminopyridines / chemical synthesis*
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Aminopyridines / pharmacokinetics
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Aminopyridines / pharmacology
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Animals
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Binding Sites
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Carboxypeptidase B2 / antagonists & inhibitors*
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Carboxypeptidase B2 / chemistry
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Dogs
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Fibrinolytic Agents / chemical synthesis*
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Fibrinolytic Agents / pharmacokinetics
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Fibrinolytic Agents / pharmacology
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology
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In Vitro Techniques
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Microsomes / metabolism
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Models, Molecular
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Propionates / chemical synthesis*
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Propionates / pharmacokinetics
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Propionates / pharmacology
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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3-(2-aminopyridin-5-yl)-2-(1-isopentylimidazol-4-yl)propanoic acid
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Acetates
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Aminopyridines
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Fibrinolytic Agents
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Imidazoles
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Propionates
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Protease Inhibitors
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Carboxypeptidase B2