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

Area of Science:

• Biochemistry
• Pharmacology
• Immunology

Background:

• Factor XIIa (FXIIa) is a serine protease crucial for coagulation and inflammation.
• Existing FXIIa inhibitors, primarily 1,2,4-triazol-5-amine derivatives, face challenges with plasma stability and reversible target engagement.
• These limitations hinder their therapeutic development.

Purpose of the Study:

• To design and optimize novel FXIIa inhibitors with improved properties.
• To address the limitations of previous FXIIa inhibitor classes.
• To evaluate the therapeutic potential of a novel inhibitor, F38, in preclinical models.

Main Methods:

• Structure-guided optimization of FXIIa inhibitors.
• Design of novel derivatives based on a tricyclic scaffold.
• Biochemical assays to determine FXIIa inhibition (IC50).
• Assessment of anticoagulant and anti-inflammatory activities.
• Evaluation in a lipopolysaccharide (LPS)-induced sepsis mouse model.

Main Results:

• A novel compound, F38, was developed exhibiting irreversible binding to FXIIa.
• F38 demonstrated potent FXIIa inhibition with an IC50 of 2 nM.
• Enhanced anticoagulant activity (EC1.5X = 11 μM) and anti-inflammatory effects were observed.
• F38 significantly reduced mortality in a mouse model of LPS-induced sepsis.

Conclusions:

• F38 represents a promising FXIIa inhibitor with a mechanistic shift towards irreversible binding.
• The compound exhibits potent inhibition, anticoagulant, and anti-inflammatory properties.
• F38 shows significant therapeutic potential in sepsis models, warranting further preclinical investigation.