Abstract
Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further in vivo efficacy studies in thrombosis models.
MeSH terms
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Animals
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Aza Compounds / chemical synthesis
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Aza Compounds / metabolism
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Aza Compounds / pharmacology*
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Carboxypeptidase B2 / antagonists & inhibitors*
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Carboxypeptidase B2 / metabolism
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Catalytic Domain
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Cyclic P-Oxides / chemical synthesis
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Cyclic P-Oxides / metabolism
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Cyclic P-Oxides / pharmacology*
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Fibrinolysis / drug effects
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Fibrinolytic Agents / chemical synthesis
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Fibrinolytic Agents / metabolism
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Fibrinolytic Agents / pharmacology*
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Humans
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Male
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Molecular Docking Simulation
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Molecular Structure
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Phosphinic Acids / chemical synthesis
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Phosphinic Acids / metabolism
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Phosphinic Acids / pharmacology*
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / metabolism
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Protease Inhibitors / pharmacology*
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Protein Binding
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Aza Compounds
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Cyclic P-Oxides
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Fibrinolytic Agents
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Phosphinic Acids
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Protease Inhibitors
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Carboxypeptidase B2