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Novel Factor XIa inhibitor Compound 32 doubles aPTT and prevents thrombosis in preclinical models.
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Demonstrates the antithrombotic efficacy of selective peptidomimetic factor XIa inhibitors in animal models, suggesting a target for safer anticoagulants.
Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, 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, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar 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 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.
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Lin et al. (2006) studied Venous thrombosis. Peptidomimetic inhibitors of Factor XIa (Compound 32) was evaluated on Activated partial thromboplastin time in human plasma and efficacy in a rat model of venous thrombosis. Peptidomimetic Factor XIa inhibitor Compound 32 doubled activated partial thromboplastin time in human plasma at 2.4 microM and showed efficacy in a rat venous thrombosis model.
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