Discovery of BT-114143, a Novel and Potent Phosphoric Acid-Containing Small-Molecule Plasminogen Activation Inhibitor for Hyperfibrinolysis

Abstract

Fibrinolysis, the natural process of blood clot dissolution regulated by plasmin, plays a crucial role in preserving vascular health. Nevertheless, if this process becomes hyperactive, it can lead to severe bleeding episodes, particularly in instances of traumatic injuries. Conventional antifibrinolytics such as ε-aminocaproic acid (EACA) and tranexamic acid (TXA) exhibit limited impact attributed to their modest potency. The substantial dosage volume necessary for effectiveness, along with safety concerns, especially when administered in high doses, further constrains their usage. In response to these challenges, we have engineered BT-114143, an innovative plasminogen activation inhibitor featuring a phosphoric acid functional group. Crafted through structure-based drug design and nonclassical bioisosteres, BT-114143 has demonstrated significant antifibrinolytic activity and target selectivity in extensive preclinical studies. Presently, BT-114143 is in Phase Ib clinical trials in China (CTR20222910), representing a noteworthy progression in antifibrinolytic therapy.