Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1<i>H</i>)‑one as the P2′ Moiety

Structure–activity relationship optimization of phenylalanine P1′ and P2′ regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2′ group enhanced FXIa affinity and metabolic stability. Incorporation of an <i>N</i>-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor <b>13</b> with a FXIa <i>K</i>_i of 0.04 nM and an aPTT EC_2<i>x</i> of 1.0 μM. Dose-dependent efficacy (EC₅₀ of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation