Targeting the S2 Subsite Enables the Structure-Based Discovery of Novel Highly Selective Factor XIa Inhibitors

FXIa
inhibition has been a promising strategy for treating thrombotic
diseases. Up to date, many small-molecule FXIa inhibitors have been
identified; however, most of them exhibit undesirable selectivity
over the homologous plasma kallikrein (PKal). By employing structure-based
drug design strategies, we identified many novel selective FXIa inhibitors
that have extra interactions with the S2 subsite of FXIa. Among them,
compound 35 displayed good inhibitory activity against
FXIa and high selectivity over PKal and even several other serine
proteases. Additionally, 35 showed significant anticoagulant
activity toward the intrinsic pathway without affecting the extrinsic
pathway. In vivo, 35 exhibited significant antithrombotic
activity without increasing the bleeding risk and obvious toxicity
in mice, demonstrating that it could be a promising candidate for
further research. This study first demonstrates the importance of
the S2 subsite of FXIa, paving the way to design highly selective
FXIa inhibitors for clinical uses.