Discovery of a potent parenterally administered factor XIa inhibitor with hydroxyquinolin-2(1H)-one as the P2′ moiety

Article abstract of DOI:10.1021/acsmedchemlett.5b00066

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 N-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 13 with a FXIa K_i of 0.04 nM and an aPTT EC_2x of 1.0 μM. Dose-dependent efficacy (EC₅₀ of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.