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

作者：Yang Zong, Zhuo Lei, Shang‐Bo Yu, Ling-Yu Zhang, Yan Wu, Ke Feng, Qiao‐Yan Qi, Yamin Liu, Ya-Jie Zhu, Peng Guo, Wei Zhou, Dan‐Wei Zhang, Zhan‐Ting Li · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.3c02224 · 被引用次数：13 · 研究领域：Heparin-Induced Thrombocytopenia and Thrombosis、Blood Coagulation and Thrombosis Mechanisms、Proteoglycans and glycosaminoglycans research

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.