Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI bythrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade.To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selectivepeptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed lownanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity.The X-ray structure of one of these inhibitors,
36, demonstrates its unique binding interactions with FXIa.Compound
32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4
Mand was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significantrole in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.