Selective Inhibition of Platelet Aggregation and Antithrombotic Activity of BIBU52: Targeting the GPIIb/IIIa Receptor

The study delves into the platelet aggregation inhibition by targeting the glycoprotein IIb/IIIa receptor, also known as αIIbβ3 integrin, which plays a crucial role in platelet activation and aggregation. A new nonpeptidic molecule, BIBU52, was investigated for its ability to block this receptor both in vitro and in vivo.

BIBU52 demonstrated competition with [125I]fibrinogen for binding to human platelets in a calcium and pH-dependent manner, with an IC50 of 35 +/- 12 nM. It effectively inhibited platelet aggregation induced by collagen, adenosine diphosphate (ADP), and a thrombin receptor-activating peptide (TRAP) with respective IC50 values. The effect of BIBU52 was highly species-specific, showing activity in primates but not in rats.

The molecule's selectivity for GPIIb/IIIa over other adhesion molecules was confirmed through a human endothelial cell adhesion assay, where BIBU52 did not affect the adhesion of human endothelial cells to various matrices even at high concentrations.

In vivo antithrombotic effects were assessed in animal models of arterial thrombus formation. BIBU52 exhibited dose-dependent inhibition of thrombus formation in guinea pigs and pigs, outperforming other treatments like acetylsalicylic acid and heparin. In marmoset monkeys, a low dose of BIBU52 was sufficient to prevent recurrent arterial thrombosis. The molecule also showed a transient effect on sublingual bleeding time without other significant hemodynamic impacts.

The research concludes that BIBU52 is a potent and selective antagonist for the human GPIIb/IIIa receptor, capable of significantly inhibiting platelet aggregation in vitro and ex vivo, as well as preventing arterial thrombus formation in vivo. This suggests its potential as an effective therapeutic agent for thromboembolic syndromes.