Key result
Novel factor Xa inhibitor SE170 shows potent in vivo efficacy in a rabbit thrombosis model.
Why the study?
Factor Xa plays a vital role in thrombosis, and there is a need to develop potent and selective inhibitors for therapeutic use.
A novel amidino bicyclic Factor Xa inhibitor demonstrated potent, selective in vitro inhibition and in vivo antithrombotic efficacy in a preclinical rabbit model.
These in vitro fXa inhibitors merit preclinical testing; leaves open clinical translation and comparative efficacy.
Thrombotic diseases are a major cause of death and morbidity. Factor Xa (fXa) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of fXa inhibitors incorporating an amidino 6,5-fused bicyclic moiety at the P1 position has been designed and synthesized based on molecular modeling studies. Structure-activity relationship (SAR) studies have led to selective subnanomolar fXa inhibitors. The most potent fXa inhibitor in this series (72, SE170) has a potent inhibition constant (K(i) = 0.3 nM), is 350-fold selective for fXa over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID(50) = 0.14 micromol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with fXa has been proposed based on modeling with human des-Gla-fXa.
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Han et al. (2000) studied Thrombotic diseases. Amidino bicyclic factor Xa inhibitors (e.g., 72, SE170) was evaluated on Factor Xa inhibition and in vivo efficacy in a rabbit arterio-venous thrombosis model. A novel amidino bicyclic factor Xa inhibitor (72, SE170) demonstrated potent inhibition (Ki = 0.3 nM) and in vivo efficacy in a rabbit thrombosis model (ID50 = 0.14 micromol/kg/h).
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