SR-121787, A NEW ORALLY-ACTIVE FIBRINOGEN RECEPTOR ANTAGONIST

The aim of this study was to describe the pharmacological properties o f SR 121787, a new antiaggregating drug which is metabolized ill vivo into SR 121566, a potent non-peptide antagonist of Gp IIb/IIIa. lit vi tro, SR 121566 antagonized the binding of [I-125]-fibrinogen (IC50 = 1 9.8 +/- 6.3 nM) and of [I-125]-L-692,884. an RGD-containing peptide (I C50 = 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 mu M. Adhe sion of human platelets to adhesive proteins was inhibited by SR 12156 6 (IC50 = 40.3 +/- 2.5 nM) only when Gp IIb/IIIa and fibrinogen were i nvolved. No effect was found with regard to other adhesive proteins an d/or other integrins. SR 121787 demonstrated a potent and sustained an tiaggregating effect when administered intravenously to baboons at a d ose 50 mu g/kg, and eight hours after the administration of 100 mu g/k g, ADP-induced aggregation was still strongly inhibited (more than 80% ). A single oral administration of 2 mg/kg sf SR 121787 produced a nea rly complete inhibition of platelet aggregation for up to 8 h (ED50 at 8 h = 193 +/- 20 mu g/kg), a significant residual antiaggregating act ivity being still observed 24h after the administration. When administ ered orally to rabbits, SR 121787 exhibited a potent antiaggregating ( ED50 = 2.3 +/- 0.3 mg/kg) and antithrombotic activity in an arterio-ve nous shunt thrombosis model (ED50 = 10.4 +/- 0.8 mg/kg). After oral an d IV administration, SR 121787 was well tolerated suggesting that SR 1 21787, the most potent and long lasting orally active Gp IIb/IIIa anta gonist described to date, is a promising antithrombotic compound.