Discovery methodology for the development of direct factor VIIa inhibitors.
INTRODUCTION
Heparin and warfarin have historically been the only antithrombotics available. Recently, however, newer anticoagulants have been developed. Factor VIIa (fVIIa) inhibitors represent one of the new and potentially exciting classes of anticoagulants currently under development. Indeed, several methodologies have been used to develop fVIIa inhibitors.


AREAS COVERED
The authors highlight some of the methologies applied for the discovery of fVIIa inhibitors including phage display, isolation of endogenous peptides from hematophagous animals and the use of the 1,5-benzothiazepine molecular scaffolds and screens of large chemical libraries previously used to identify other serine protease inhibitors. Although these screens were intended to identify thrombin and factor Xa inhibitors, the compounds often had concomitant fVIIa activity. The authors also discuss the utilization of medical chemistry techniques for the discovery of these compounds.


EXPERT OPINION
FVIIa inhibitors represent a viable option for the development of new anticoagulants. There are theoretical advantages that fVIIa inhibitors may possess over existing anticoagulants and highly specific inhibitors that possess oral bioavailability and low bleeding risk may succeed.
['Henry|Brian L|BL|', 'Desai|Umesh R|UR|']
D000818:Animals D000925:Anticoagulants D001682:Biological Availability D015195:Drug Design D015942:Factor VIIa D006470:Hemorrhage D006801:Humans D013841:Thiazepines
factor VIIa anticoagulants coagulation small molecule inhibitors tissue factor