Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups

Factor XIa (FXIa) inhibitors are
promising novel anticoagulants,
which show excellent efficacy in preclinical thrombosis models with
minimal effects on hemostasis. The discovery of potent and selective
FXIa inhibitors which are also orally bioavailable has been a challenge.
Here, we describe optimization of the imidazole-based macrocyclic
series and our initial progress toward meeting this challenge. A two-pronged
strategy, which focused on replacement of the imidazole scaffold and
the design of new P1 groups, led to the discovery of potent, orally
bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover,
pyridine-based macrocycle 19, possessing the phenylimidazole
carboxamide P1, exhibited excellent selectivity against relevant blood
coagulation enzymes and displayed antithrombotic efficacy in a rabbit
thrombosis model.