Abstract 13510: Discovery of Non-Heparin, Small, Allosteric, Factor XIa Inhibitors
Current anticoagulants, which target either thrombin or factor Xa, are plagued with a number of drawbacks and adverse effects, e.g., enhanced risk of bleeding. Several lines of evidence support that factor XIa is a promising target for developing safer anticoagulants. We reasoned that mimicking heparin binding to factor XIa should provide an excellent starting point for developing small molecule mimetics as allosteric inhibitors of this important enzyme. Following a small screening study, we identified sulfated gallic acid-based molecules as promising anticoagulants. Sulfated gallic acid-based SPGG potently inhibited factor XIa in vitro with an IC50 of 1.2 μg/ml. It selectively doubled the human plasma clotting time in an aPTT assay at 96 μg/ml. Michaelis-Menten kinetics indicated that SPGG reduced the forward rate constant of substrate hydrolysis by factor XIa without significantly affecting the Michaelis constant suggesting an allosteric mechanism of inhibition. SPGG inhibited factor XIa selectively over several other proteases of both coagulation and digestive systems with a preference of at least 200-fold. Thromboelastography studies showed that SPGG effectively extended human whole clotting at 135 μg/ml. No chemically synthesized molecule has been discovered so far that exhibits such high potency, selectivity, and an allosteric factor XIa inhibition mechanism. This work opens up a major route to novel, synthetic, allosteric small molecule factor XIa inhibitors that are clinically relevant.
- © 2012 by American Heart Association, Inc.