Coagulation factor Xa (fXa) is a particularly attractive target for the development of effective and safe anticoagulants. In this study, novel 2,3-dihydroquinazolin-4(1H)-one derivatives were designed as potential fXa inhibitors based on anthranilamide structure which has been reported in our previous research. The experimental data showed that most of the designed compounds exhibited significant in vitro potency against fXa. Among them, compound 8e displayed the strongest potency against fXa with the IC50 value of 21 nM and highly selectivity versus thrombin (IC50 = 67 μM) and excellent in vitro antithrombotic activity with its 2 × PT value of 1.2 μM and 2 × aPTT value of 0.6 μM. In addition, 8e also displayed excellent in vivo antithrombotic activity in the rat arteriovenous shunt (AV-SHUNT) model. The bleeding risk evaluation showed that 8e had a similar safety profile as that of betrixaban. All results demonstrated that compound 8e could be considered as a potential fXa inhibitor for the prevention and treatment of thromboembolic diseases.
Keywords: Anticoagulant; Arteriovenous shunt; Bleeding risk; Factor Xa; Thromboembolic diseases; fXa inhibitor.
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