Design, synthesis, and biological evaluation of substituted oxopyridine derivatives as selective FXIa inhibitors

Abstract

To explore selective FXIa inhibitors, a series of compounds were rationally designed with computer-aid drug design (CADD) and synthesized by introducing hydrophobic P1 fragments which could strengthen interaction to S1 pocket of FXIa and weaken interaction to plasma kallikrein. All the compounds were tested for the inhibition against FXIa and some of them were further evaluated in plasma kallikrein selectivity assay and clotting assay. Compound 4c demonstrated excellent in vitro potency, good membrane permeability and higher selectivity than Asundexian. Furthermore, 4c showed excellent pharmacokinetics property in rats after intravenous or oral administration. The results indicate that 4c can serve as a novel FXIa inhibitor that has potential clinical applications in patients.