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

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Activated factor XI (FXIa) inhibitors represent a novel class of anticoagulants with a potentially lower bleeding risk compared to existing therapies.
• Developing potent FXIa inhibitors with favorable oral bioavailability remains a significant challenge in anticoagulant drug discovery.

Purpose of the Study:

• To discover potent and orally bioavailable activated factor XI inhibitors.
• To explore the use of nonclassical interactions to enhance binding affinity, cellular permeability, and oral bioavailability.

Main Methods:

• Utilized structure-based drug design and medicinal chemistry strategies, starting from a pyridine N-oxide-based inhibitor.
• Modified lead compounds by altering linker moieties and substituents in key binding regions to optimize interactions.
• Incorporated nonclassical interactions, such as polar C-H···water hydrogen bonds, to improve molecular properties.

Main Results:

• Discovered a highly potent FXIa inhibitor, compound 3f, with a dissociation constant (Ki) of 0.17 nM.
• Achieved significant oral bioavailability in preclinical species: 36.4% in rats, 80.5% in dogs, and 43.0% in monkeys.
• Demonstrated a dose-dependent antithrombotic effect in a rabbit arteriovenous shunt thrombosis model.

Conclusions:

• The developed FXIa inhibitor 3f exhibits promising potency, oral bioavailability, and antithrombotic activity.
• Nonclassical interactions are effective strategies for enhancing the potency and pharmacokinetic properties of FXIa inhibitors.
• This discovery offers a potential new therapeutic option for anticoagulation with an improved safety profile.