A naphthalimide derivative exerts potent antiplatelet and antithrombotic activities without a bleeding tendency.

BACKGROUND

Bleeding is the inherent adverse effect of antiplatelet drugs that has limited their use in the prevention of secondary heart attack and stroke. Thus, finding a novel antiplatelet drug with antithrombotic activities while preserving hemostatic function remains a crucial issue. Here, we screened naphthalimide derivatives that we previously synthesized and identified a novel derivative compound , which has a more potent antithrombotic effect and has no effect on bleeding cessation. This study is aimed to determine the antiplatelet mechanism of compound and further test whether compound is a safer and more potent antithrombotic agent.

METHODS

Platelet aggregation, flow cytometry and immunoblotting were used to determine the antiplatelet effect of compound . The study of thrombus formation of mesenteric venules in mice was used to evaluate the antithrombotic effect of compound .

RESULTS

Compound selectively inhibited collagen-mediated platelet aggregation and markedly prevented thrombus formation without bleeding tendency. Compound also inhibited glycoprotein VI (GPVI) downstream signaling, such as Fyn and Lyn, phospholipase C gamma 2, protein kinase C. Moreover, a surface plasmon resonance assay indicated that compound may directly bind to GPVI, thereby interrupting the interaction of collagen and GPVI. Compound also effectively attenuates collagen-induced granule release, calcium mobilization, and GPIIbIIIa activation.

CONCLUSION

These findings indicate that compound can selectively inhibit GPVI, eventually suppressing platelet activation and thrombus formation while preserving hemostasis. Compound is a GPVI antagonist and safe antiplatelet agent. Compound also has therapeutic potential for treating cardiovascular diseases.