AZD0837, currently in clinical development, is a once-daily oral
anticoagulant that is bioconverted to
AR-H067637, a selective, reversible
direct thrombin inhibitor (DTI). When developing a new DTI, the antithrombotic effects are commonly investigated in in vivo animal models; this report shows the effect of
AR-H067637 in venous and arterial
thrombosis and
bleeding models in anaesthetised rats.
Thrombus formation was induced by topical application of
ferric chloride to the carotid artery or to the caval vein with partial stasis. Cutaneous incision bleeding time and muscle transection blood loss were assessed, with or without
acetylsalicylic acid (ASA). Activated partial thromboplastin time (APTT),
ecarin coagulation time (ECT) and
thrombin coagulation time (TCT) were used as plasma
biomarkers of
anticoagulant effect.
Dalteparin was used as a reference compound.
AR-H067637, given by continuous infusion, displayed a dose-dependent antithrombotic effect, with 50% inhibition (IC50) of
thrombus size in venous and arterial
thrombosis models obtained at plasma concentrations of 0.13 μM and 0.55 μM, respectively, without increased
bleeding. Dose-dependent increased
bleeding and blood loss were seen at plasma concentrations ≥1 μM
AR-H067637. At the highest
AR-H067637 plasma concentration tested, bleeding time and blood loss increased two and four times the vehicle group. Addition of ASA moderately potentiated bleeding time and blood loss. APTT, ECT and TCT were dose-dependently prolonged. These studies demonstrate that the DTI
AR-H067637 inhibits
thrombus formation in rat venous and arterial
thrombosis models with no or minor increases in
bleeding.