Discovery of the First Highly Potent, Selective, Irreversible Small-Molecule Factor XIIa Inhibitor for Treating Sepsis.

Factor XIIa (FXIIa), a key serine protease at the intersection of coagulation and inflammation, has emerged as an attractive therapeutic target in recent years. To date, 1,2,4-triazol-5-amine-based covalent inhibitors constitute the most extensively investigated class of FXIIa inhibitors. However, the majority of these compounds have not progressed further in development, largely due to limitations such as insufficient plasma stability and transient, reversible target engagement. To address these shortcomings, we conducted structure-guided optimization and designed a series of derivatives featuring a distinct tricyclic scaffold. Among these, F38 exhibited a mechanistic shift toward irreversible binding, resulting in markedly improved FXIIa inhibition (IC50 = 2 nM) along with enhanced anticoagulant activity (EC1.5X = 11 μM) and anti-inflammatory effects. Notably, F38 demonstrated significant therapeutic benefit in a mouse model of LPS-induced sepsis, substantially reducing mortality and highlighting its promise as a candidate for further preclinical development.