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

Abstract

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 (K i = 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.

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

“…For example, we found that dual inhibition against FXIa and PKal slightly increased the bleeding risk in mice, whereas Xu et al. proposed that the dual inhibition may contribute to a synergistic anticoagulant effect . Therefore, the precise benefits and drawbacks of dual FXIa/PKal inhibition must be determined in the future.…”

“…For example, we found that dual inhibition against FXIa and PKal slightly increased the bleeding risk in mice, 65 whereas Xu et al proposed that the dual inhibition may contribute to a synergistic anticoagulant effect. 119 Therefore, the precise benefits and drawbacks of dual FXIa/PKal inhibition must be determined in the future. Early stage covalent SMFIs had poor selectivity over trypsin, but this has recently been improved significantly (for example, EP-7041 showed over 500-fold selectivity over trypsin).…”

“…Remarkably, 50 did not have significant hERG ion channel liability and did not form reactive metabolites in human LM. In a rabbit arteriovenous shunt model, it demonstrated significant antithrombotic activity in a dose-dependent manner …”

“…In a rabbit arteriovenous shunt model, it demonstrated significant antithrombotic activity in a dose-dependent manner. 119 5.1.4. Macrocyclic FXIa Inhibitors.…”

Medicinal Chemistry of Drugs with N-Oxide Functionalities

“…Factor XIa is a blood coagulation protease, and a pyridine-N-oxide derivative has been shown to interact favorably with the oxyanion binding site in the enzyme via its pyridine N-oxide core (Figure 6). 103 Minoxidil (Figure 7) is a prodrug that was originally developed to treat high blood pressure. However, it is commonly used to treat hair loss, particularly in androgenetic alopecia, also known as hereditary hair loss.…”