Covalent inhibitors of human blood coagulation factors as new anticoagulant drugs

Thrombosis, a major cause of mortality worldwide, is linked to myocardial infarction and ischemic stroke [1]. Developing new antithrombotic drugs is critical, especially since current direct oral anticoagulants like dabigatran and rivaroxaban are associated with risks of internal bleeding [2]. New anticoagulants that target alternative enzymes in the coagulation cascade or use different mechanisms on existing targets are essential. FXIIa is a promising, safe target involved in thrombosis but not essential for hemostasis [3,4]. Alternatively, targeting thrombin with a specific covalent inhibitor could potentially prevent bleeding complications [5]. To develop new antithrombotic agents, we synthesized and screened a series of acylated aminotriazoles and aminopyrazoles against key human serine proteases. We identified compounds that are low nanomolar inhibitors of FXIIa (e.g., 1) and thrombin (e.g., 2), exhibiting minimal impact on other serine proteases. These compounds also demonstrated in vitro anticoagulant effects, notably extending PT and aPTT in human plasma. Additionally, using the mass-shift assay, we confirmed the covalent reversible mechanism of action of these compounds [6-8].