Synthesis of pyrrolo[3,2-d]pyrimidineone derivatives as novel FXa inhibitors

A series of pyrrolo[3,2-d]pyrimidineone compounds have been designed and synthesized as novel FXa inhibitors. Bioassay of the tested compounds showed moderate to excellent anticoagulant potency in vitro. Further FXa inhibitory and bioactivity evaluation in rats, the FeCl3-induced venous thrombosis model, showed that the compound 17a has good FXa inhibitory activity (IC50 = 1.57 nM) and in vivo antithrombotic potency. The anticoagulant effects of compound 17a were dose dependent whether in vitro or in vivo. The results further confirmed our hypothesis that the large conjugated structure is an ideal skeleton binding FXa.

Automated summary

A series of novel FXa inhibitors, pyrrolo[3,2-d]pyrimidineone compounds, were designed and synthesized. The tested compounds showed moderate to excellent anticoagulant potency in vitro. In rats, further evaluation revealed that compound 17a exhibited good FXa inhibitory activity (IC50 = 1.57 nM) and in vivo antithrombotic potency. The dose-dependent anticoagulant effects of compound 17a were confirmed both in vitro and in vivo.