SR 121787, a New Orally Active Fibrinogen Receptor Antagonist

Pierre Savi; Alain Badorc; Alain Lalé; Marie-Françoise Bordes; Josette Bornia; Catherine Labouret; André Bernat; Paul de Cointet; Peter Hoffmann; Jean-Pierre Maffrand; Jean-Marc Herbert

doi:10.1055/s-0037-1615231

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 80(03): 469-476
DOI: 10.1055/s-0037-1615231

Rapid Communications

Schattauer GmbH

SR 121787, a New Orally Active Fibrinogen Receptor Antagonist

Authors

Pierre Savi

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Alain Badorc

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Alain Lalé

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Marie-Françoise Bordes

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Josette Bornia

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Catherine Labouret

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
André Bernat

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Paul de Cointet

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Peter Hoffmann

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Jean-Pierre Maffrand

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
Jean-Marc Herbert

¹From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France

Abstract

Summary

The aim of this study was to describe the pharmacological properties of SR 121787, a new antiaggregating drug which is metabolized in vivo into SR 121566, a potent non-peptide antagonist of Gp IIb/IIIa. In vitro, SR 121566 antagonized the binding of [¹²⁵I]-fibrinogen (IC₅₀ = 19.8 ± 6.3 nM) and of [¹²⁵I]-L-692,884, an RGD-containing peptide (IC₅₀ = 291 ± 96 nM) to activated human platelets. SR 121566 inhibited the aggregation of human platelets induced by ADP, collagen, thrombin, arachidonic acid and PAF at concentrations lower than 0.1 μM. Adhesion of human platelets to adhesive proteins was inhibited by SR 121566 (IC₅₀ = 40.3 ± 2.5 nM) only when Gp IIb/IIIa and fibrinogen were involved. No effect was found with regard to other adhesive proteins and/or other integrins. SR 121787 demonstrated a potent and sustained antiaggregating effect when administered intravenously to baboons at a dose 50 μg/kg, and eight hours after the administration of 100 μg/kg, ADP-induced aggregation was still strongly inhibited (more than 80%). A single oral administration of 2 mg/kg of SR 121787 produced a nearly complete inhibition of platelet aggregation for up to 8 h (ED₅₀ at 8 h = 193 ± 20 μg/kg), a significant residual antiaggregating activity being still observed 24h after the administration. When administered orally to rabbits, SR 121787 exhibited a potent antiaggregating (ED₅₀ = 2.3 ± 0.3 mg/kg) and antithrombotic activity in an arterio-venous shunt thrombosis model (ED₅₀ = 10.4 ± 0.8 mg/kg). After oral and IV administration, SR 121787 was well tolerated suggesting that SR 121787, the most potent and long lasting orally active Gp IIb/IIIa antagonist described to date, is a promising antithrombotic compound.

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References

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