Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

Unfractionated
heparin (UFH) and low-molecular-weight heparins
(LMWHs) are widely applied for surgical procedures and extracorporeal
therapies, which, however, suffer bleeding risk. Protamine, the only
clinically approved antidote, can completely neutralize UFH, but only
partially neutralizes LMWHs, and also has a number of safety drawbacks.
Here, we show that caltrop-like multicationic small molecules can
completely neutralize both UFH and LMWHs. In vitro and ex vivo assays
with plasma and whole blood and in vivo assays with mice and rats
support that the lead compound is not only superior to protamine by
displaying higher neutralization activity and broader therapeutic
windows but also biocompatible. The effective neutralization dose
and the maximum tolerated dose of the lead compound are determined
to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise
for further preclinical studies.