A Selective Small Molecule Factor VIIa Inhibitor, CRA-027483, Suppresses Acute Inflammation in Mice (original) (raw)

Blood

Abstract

Factor VIIa (FVIIa) is a well known member of the extrinsic coagulation cascade and therefore an attractive therapeutic target for thrombosis. CRA-027483 is a potent, selective, reversible small molecule inhibitor of human FVIIa that displays anti-thrombotic activities in vitro and in vivo. In addition to the well-characterized role of the FVIIa/tissue factor (TF) complex in coagulation, FVIIa/TF complex has more recently been implicated in inflammation via intracellular signaling initiated by the cleavage of protease activated receptors (PARs) by the complex. Therefore, we assessed the ability of CRA-027483 to inhibit acute inflammation using a mouse model of endotoxemia. The compound was delivered subcutaneously one hour prior to LPS challenge and serum or plasma was harvested at varying time points post-challenge. Soluble mediators of coagulation and inflammation induced by LPS were measured by ELISA. Additionally, prothrombin time (PT) and compound exposure were determined. CRA-...

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