Discovery of Highly Selective, Potent, Covalent, and Orally Bioavailable Factor XIIa Inhibitors for the Treatment of Thrombo-Inflammation

Thrombo-inflammation is closely associated with a few
severe cardiovascular
and infectious diseases. Factor XIIa (FXIIa) in the intrinsic coagulation
pathway plays a pivotal role in the development of thrombo-inflammation
and its inhibition has emerged as a potential therapeutic approach
for thrombo-inflammatory disorders. Nonetheless, as of now, few small-molecule
FXIIa inhibitors have demonstrated notable effectiveness against thrombo-inflammation,
with none progressing into clinical stages. Herein, we present potent,
covalent, reversible, and selective small-molecule FXIIa inhibitors
such as 4a and 4j obtained through structure-based
drug design. Compounds 4a and 4j showed
significant anticoagulation and substantial anti-inflammatory effects in vitro, coupled with exceptional plasma stability. Furthermore,
in carrageenan-induced thrombosis models, 4a and 4j demonstrated remarkable dual antithrombotic and anti-inflammatory
activity when administered orally. Compound 4j exhibited
a favorable safety profile without obvious tissue toxicity in mice,
suggesting its potential as an oral therapeutic option for thrombo-inflammation.