Characterization of N,N'-bis(3-picolyl)-4-methoxy-isophtalamide (picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets.

Picotamide (G137 or N,N'-bis[3-picolyl]-4-methoxy-isophtalamide), a drug which has shown platelet inhibitory effects in vitro and ex vivo, was investigated for its mechanism of action on human platelets in vitro. This compound suppresses the aggregation of human platelets induced by arachidonic acid (IC50: 1.8 x 10(-5) M), low-dose collagen (IC50: 3.5 x 10(-4) M), U46619 (IC50: 1 1.4 x 10(-4) M) and by authentic TxA2 (IC50: 1 x 10(-4) M), without affecting the aggregation induced by A23187 or primary aggregation by ADP. Picotamide inhibits dose-dependently TxA2 synthesis by platelets (IC50: 1.5 x 10(-4) M) and enhances the formation of PGE2. Picotamide-treated platelets also favour the formation of PGI2 by aspirinated endothelial cells; in addition, the drug appears to exert a direct stimulatory effect on PGI2-synthesis, at least at high concentrations. Finally, in platelet-rich plasma stimulated with arachidonic acid, picotamide increases intraplatelet cAMP while no effects on cAMP are detected in unstimulated platelets. In conclusion, picotamide is a dual thromboxane-synthase inhibitor/thromboxane-receptor antagonist in human platelets and introduces a new class of agents potentially useful in antithrombotic therapy.