Mechanism of action: Thrombin inhibitor
AZ12971554 is a potent inhibitor of human thrombin with Ki = 0.3nM and activated partial thromboplastin time (APTT) IC50 = 0.68µM and Ecarin clotting time (ECT) IC50 = 0.16µM in human plasma.
AZ12971554 demonstrates good selectivity towards other serine proteases with Trypsin I = 400, Trypsin IV = 100, FVIIa = 12750, FIXa = 4250, FXa = 675, FXIa = 1150, Kallekrein = 4700, t-PA = 775, Plasmin = 3450 and APC >11000 times selectivity. In addition, AZ12971554 showed <50% inhibition at 10µM against 100 targets in a general selectivity screen with Thromboxane A2 (IC50 = 14µM) and Cathepsin G (IC50 = 1µM) being the most potent hits.
AZ12971554 shows good efficacy in vivo in venous and arterial thrombosis models in the rat with EC50 = 0.18 and 0.5µM respectively following bolus/infusion administration. AZ12971554 is orally available and well tolerated after repeated administration in both rats and dogs and is consequently suitable for chronic use. Due to the biological mechanism, bleeding is an expected side effect at high exposure (plasma concentrations >1µM).
A prodrug of AZ12971554 has been administered orally to man in a limited Phase 1 study resulting in good bioavailability of the active compound.