Synthetic inhibitors of coagulation factor Xa.
The antithrombotic efficacy of low molecular weight heparins suggest that specific inhibition of blood coagulation factor Xa (fXa) is an appropriate target for drug discovery. Clinical evidence also supports the effectiveness of warfarin, an orally bioavailable non-specific anticoagulant. The reported synthetic fXa inhibitors are directed towards the enzyme active site, and have been mostly non-inhibitory against closely related proteases, such as thrombin and activated protein C. Several groups have reported potent lead compounds with in vitro human fXa inhibitory activities (Ki and IC50) in the nanomolar range. Preclinical data on oral bioavailability, plasma half-life of clearance and activity in animal models of thrombosis have been reported for a select few. In the absence of human data, it is hard to speculate if any of the inhibitors discussed here possess the proper combination of potency and bioavailability, to be an ideal fXa inhibitor drug candidate. Since the ultimate goal is to produce a 'better warfarin', reproducibility of anticoagulation with a wider ratio of antithrombotic to antihaemostatic doses will be necessary for this class of inhibitors.
Sinha
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COR Therapeutics, Inc., 256 East Grand Avenue, San Francisco, CA 94080, USA. usinha@corr.com