Discovery of Potent and Orally Bioavailable Pyridine N‑Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions

Activated factor XI (FXIa) inhibitors are promising novel
anticoagulants
with low bleeding risk compared with current anticoagulants. The discovery
of potent FXIa inhibitors with good oral bioavailability has been
challenging. Herein, we describe our discovery effort, utilizing nonclassical
interactions to improve potency, cellular permeability, and oral bioavailability
by enhancing the binding while reducing polar atoms. Beginning with
literature-inspired pyridine N-oxide-based FXIa inhibitor 1, the imidazole linker was first replaced with a pyrazole moiety
to establish a polar C–H···water hydrogen-bonding
interaction. Then, structure-based drug design was employed to modify
lead molecule 2d in the P1′ and P2′ regions,
with substituents interacting with key residues through various nonclassical
interactions. As a result, a potent FXIa inhibitor 3f (Ki = 0.17 nM) was discovered. This
compound demonstrated oral bioavailability in preclinical species
(rat 36.4%, dog 80.5%, and monkey 43.0%) and displayed a dose-dependent
antithrombotic effect in a rabbit arteriovenous shunt model of thrombosis.