Factor VIIa inhibitors: Target hopping in the serine protease family using X-ray structure determination

Selective factor VIIa–tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4–11) containing l-Gln or l-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b–f showed improved selectivity.

Graphical abstractWe succeeded in target hopping in the serine protease family using crystal structures of human FVIIa/TF in complex with peptide mimetic inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide