Phosphinanes and Azaphosphinanes as Potent and Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa)

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.