Protease form factor Xia (FXIa) is a therapeutic target for thrombosis prevention due to its well-known contribution to VTE and ischemic stroke in humans. Researchers from Janssen Pharmaceutica NV presented an antithrombotic target FXIa inhibitor obtained through a non-classical interactions strategy to improve the pharmacokinetic and pharmacological activity for the treatment of thrombosis. In the series, the potency was increased by using water-mediated hydrogen bonds to reduce polar hydrogen bond donors and using methyl to displace high-energy waters.