A Synthetic, Small Molecule, Allosteric Inhibitor of Human Factor XIa for Thrombosis.

Only a handful of anticoagulants have reached the clinic to treat and prevent thrombotic episodes in the millions of patients suffering from cardiovascular, cancer, viral (COVID-19) and metabolic diseases. In this work, we report the discovery, chemical synthesis, mechanistic biochemistry, pharmacology, and toxicology of SB-01, a novel, allosteric, human factor XIa (FXIa) inhibitor that displays potent antithrombotic activity in preclinical models. SB-01 is a synthetic, highly sulfated, aromatic agent that binds in both anion-binding exosites of hFXIa to induce inhibition of factor IX activation. SB-01 inhibited rodent arterial and venous thrombosis at doses of 6 and 3 mg/kg, respectively. Additionally, a twice-a-day regimen of 6 mg/kg SB-01 was significantly more effective (p<0.001) in preventing deep vein thrombosis in animals with lung cancer. Michaelis-Menten kinetics and competition with unfractionated heparin and polyphosphate revealed SB-01 to be an allosteric inhibitor. Critically, at the effective dose of 6 mg/kg, SB-01 did not significantly increase mouse tail bleeding time or blood loss. Further, SB-01's anticoagulation could be readily reversed with protamine sulfate, the FDA-approved antidote for heparin. Finally, SB-01 showed no major adverse effects across multiple toxicological assays including gross, cardiac, metabolic, hematological, and clinical chemistry. Overall, this work presents a structurally and functionally unique, allosteric small molecule as a highly promising candidate for safer anticoagulation.