Abstract 9383: Selective Tissue Factor/Factor VIIa Inhibitor ER-410660 and its Prodrug E5539 Have an Anti-Venous Thrombotic Effect with Low Risk of Bleeding
The “extrinsic coagulation pathway” is activated by complex formation between tissue factor (TF) and factor VIIa (FVIIa). The onset of thrombosis is associated with the specific expression of TF. Compounds that inhibit the TF/FVIIa complex might therefore have therapeutic and/or prophylactic uses for diseases associated with thrombus formation. TF/FVIIa inhibitors might also reduce the risk of bleeding as they leave the intrinsic pathway intact and so maintain normal hemostasis. We assessed this hypothesis using a series of triazolone derivatives that acted as potent and selective TF/FVIIa inhibitors. Based on human intravenous pharmacokinetic data from a microdosing study, we identified ER-410660 as a candidate for prodrug formation to improve oral availability. ER-410660 showed potent and selective inhibition of the TF/FVIIa complex with an IC50 of 5.7 nM. The compound selectively prolonged the prothrombin time (PT) in human, rhesus monkey, and rat plasma (a 50% increase of PT was obtained at 2.0, 1.7, and 19 μM, respectively). Intravenous (iv) administration of ER-410660 dose-dependently inhibited thrombin generation caused by TF-injection in the rhesus monkey with an ED50 of 40 (95% CI, 25-55) μg/kg. ER-410660 (iv) reduced venous thrombus weights in a TF-administered stasis-induced venous thrombosis model in rats with an ED50 of 0.18 (95% CI, 0.11-0.25) mg/kg. The anti-hemostatic effect of ER-410660 (iv) was evaluated in a rat tail-cut model. The total bleeding time was doubled at 7.1 (95% CI, 6.1-11) mg/kg, which was 39-fold higher than the ED50 value in the rat venous thrombosis model. E5539, an orally available form of ER-410660, was discovered by prodrug formation. Oral E5539 at doses of 3, 10, and 30 mg/kg reduced plasma thrombin-antithrombin (TAT) complex levels elevated by TF-injection in a dose-dependent manner. The TAT level was reduced to 50% of the control at an ED50 value of 12 (95% CI, 8.0-17) mg/kg. These proof-of-concept studies in animal models suggest that selective TF/FVIIa inhibitors such as ER-410660 and its prodrug E5539 could act as novel anticoagulants with a low risk of bleeding.
- © 2011 by American Heart Association, Inc.