Summary
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 anti-thrombotic 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.
Keywords AR-H067637 - bleeding - direct thrombin inhibitor - rat - venous and arterial thrombosis
