Novel strategy to boost oral anticoagulant activity of blood coagulation enzyme inhibitors based on biotransformation into hydrophilic conjugates

In this article, we propose a novel strategy towards discovery for orally active anticoagulants. This strategy is based on bioconversion from a nonamidine-type blood coagulation cascade inhibitor into the corresponding conjugate, which boosts ex vivo anticoagulant activity owing to an increase in hydrophilicity. Computational molecular modeling enabled us to rationally select a template scaffold and design a series of novel inhibitors. Our study resulted in the identification of the phenol-containing fXa inhibitor ASP8102 (14) with excellent oral anticoagulant activity, which was biotransformed into the active glucuronide 16 after oral dosing.