Characterization of a novel selective factor Xa inhibitor, DJT06001, which reduces thrombus formation with low risk of bleeding

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Abstract

Factor Xa (FXa) is a serine protease that plays key roles in linking the intrinsic and extrinsic coagulation pathways to the final common pathway. DJT06001 is an oral, highly specific and direct FXa inhibitor for the prevention and treatment of thromboembolic diseases. We characterized the compound in vitro and studied its in vivo activity in rat thrombosis models, as well as bleeding risk and Pharmacokinetics and Pharmacodynamics (PK/PD) relationship. DJT06001 inhibited free FXa with an inhibitory constant (Ki) of 0.99 nM, and exhibited >10000-fold selectivity for FXa than for other related serine proteases. DJT06001 concentration-dependently inhibited FXa activity in the prothrombinase complex with an IC50 of 2.53 nM. The concentrations for DJT06001 to double the prothrombin time (PT) and activated partial thromboplastin time (APTT) were 0.74 and 0.57 μM, respectively. Importantly, DJT06001 did not impair platelet aggregation induced by ADP, platelet activating factor (PAF) and collagen. Furthermore, DJT06001 inhibited thrombus formation in rat thrombosis models in a dose dependent manner. And in rat tail bleeding risk test, it caused less bleeding than rivaroxaban at doses that achieve the same antithrombotic effect. PK/PD studies further demonstrated that there was a good correlation between the plasma concentrations of DJT06001and its inhibition of plasma FXa activity and prolongation of PT. In conclusion, DJT06001 was shown to be a potent and specific FXa inhibitor with excellent PK/PD profiles and it could be developed as a new anticoagulant for the management of thromboembolic diseases.

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