Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807834 (CI-1031)

ZK-807834 (also known as CI-1031) is a small molecule that potently and selectively inhibits Factor Xa. Studies in animals have shown that ZK-807834 attenuates thrombosis and thrombus progression after fibrinolysis and exhibits an increased antithrombotic-to-bleeding risk ratio compared with conventional agents. The present study describes the human in vitro anticoagulant and pharmacodynamic profile ZK-807834. Consistent with its selective inhibition of Factor Xa, ZK-807834 in the range of 0.3-0.5 microM prolonged prothrombin time (PT) and activated partial thromboplastin time (aPPT) twofold without affecting thrombin time (TT). Intersubject variability of in vitro anticoagulant activity was nominal and gender-independent. ZK-807834 inhibited Factor Xa in clot-bound prothrombinase with an average IC50 of 10+/-7 (S.D.) nM. ZK-807834 exhibited no direct effect on ADP- or collagen-induced platelet aggregation. Based on the potency and specificity, ZK-807834 may represent an important advance in the development of selective and safe antithrombotics.