molecules of the month

Context. “Compound 3f” (Janssen) is an oral Factor XIa (FXIa) inhibitor being developed for thromboembolic diseases. The suitability of FXIa as a target in the development of anticoagulation agents stems from observations that the coagulation factor contributes significantly to pathological blood clotting (thrombosis) but plays a negligible role in physiological blood clotting (hemostasis). Unsurprisingly, >100 patent applications covering various categories of FXIa inhibitors, from small molecules to oligonucleotides, have been filed since the 1990s (see our previously featured FXIa inhibitors asundexian, milvexian, and “compound 23”). The development of pyridine-N-oxide–based “compound 3f” presents an example of utilizing nonclassical active site interactions to modulate potency and bioavailability. The compound demonstrated strong selectivity over other coagulation proteases and had an acceptable PK, with…