Abstract 15865: Novel, Highly Selective Direct Thrombin Inhibitors: Efficacy, Safety, and Tolerability Studies

Patients with atrial fibrillation and venous thromboembolism require anticoagulation prophylaxis/treatment. Direct oral anticoagulants (DOACs) offer certain advantages over warfarin and heparins, but there remains a significant unmet need for anticoagulant agents with better risk-benefit profiles than currently available treatments. We have developed a new class of highly selective direct thrombin inhibitors (VE-DTIs) with a unique mode of action, namely reversible covalent inhibition of thrombin. These VE-DTIs demonstrate preclinical properties superior to those of the available DOACs that were tested. The VE-DTIs target thrombin with high affinity (IC50 100-fold over other serine proteases); their PK half-life and oral bioavailability are comparable to or better than the tested DOACs. The VE-DTIs prevent clot formation with efficacy similar to that of the DOACs in rodent models of arteriovenous shunt thrombosis and tissue-factor venous stasis thrombosis. In addition to their st...