Characterization of N,N’-bis(3-Picolyl)-4-Methoxy-Isophtalamide (Picotamide) as a Dual Thromboxane Synthase Inhibitor/Thromboxane A2 Receptor Antagonist in Human Platelets

P Gresele; H Deckmyn; J Arnout; G G Nenci; J Vermylen

doi:10.1055/s-0038-1646618

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1989; 61(03): 479-484
DOI: 10.1055/s-0038-1646618

Original Article

Schattauer GmbH Stuttgart

Characterization of N,N’-bis(3-Picolyl)-4-Methoxy-Isophtalamide (Picotamide) as a Dual Thromboxane Synthase Inhibitor/Thromboxane A₂ Receptor Antagonist in Human Platelets

P Gresele

¹The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium

²The Istituto di Semeiotica Medica, University of Perugia, Perugia, Italy

,

H Deckmyn

¹The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium

,

J Arnout

¹The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium

,

G G Nenci

²The Istituto di Semeiotica Medica, University of Perugia, Perugia, Italy

,

J Vermylen

¹The Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium

› Institutsangaben

Abstract

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Summary

Picotamide (G137 or N,N’-bis[3-picolyl]-4-methoxy-iso- phtalamide), 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 × 1(T5 M), low-dose collagen (IC₅₀: 3.5 × 10^-4 M), U46619 (IC₅₀: 1.4 × 10^-4 M) and by authentic TxA₂ (IC₅₀: 1 × 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 × 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.

Keywords

Antithrombotics - cAMP - Platelet inhibition - Prostacyclin

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Referenzen

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