New orally active non-peptide fibrinogen receptor (GpIIb-IIIa) antagonists: identification of ethyl 3-[N-[4-[4-[amino[(ethoxycarbonyl) imino]methyl]phenyl]-1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl]pip erid -4-yl]amino]propionate (SR 121787) as a potent and long-acting antithrombotic agent.

The platelet fibrinogen receptor GpIIb-IIIa is currently considered a target of choice for drugs used in the prevention and treatment of thrombosis. Ethyl 3-[N-[4-[4-[amino[(ethoxycarbonyl)-imino] methyl]phenyl]-1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl] piperid-4-yl] amino]propionate (6, SR 121787) is a new antiaggregating agent which generates in vivo the corresponding diacid 19d (SR 121566), non-peptide GpIIb-IIIa antagonist. In vitro, 19d inhibited ADP-induced aggregation of human and baboon platelets (IC50 = 46 +/- 11 and 54 +/- 6 nM, respectively), and on human platelets, 19d antagonized the binding of 125I-labeled fibrinogen (IC50 = 19.2 +/- 6.2 nM). Ex vivo, 8 h after an i.v. administration of 19d (100 micrograms/kg, i.v.) to baboons, ADP-induced aggregation was strongly inhibited (more than 90%). At 8 h, the ED50 value was 24 +/- 3.3 micrograms/kg), and even 24 h after the administration of a single dose of 100 micrograms/kg of 19d, platelet aggregation was still significantly inhibited (50 +/- 6% inhibition, P < 0.05). In the same species, the oral administration of 500 micrograms/kg of 6 produced a nearly complete inhibition of aggregation for up to 8 h (ED50 at 8 h was 193 +/- 20 micrograms/kg). After an oral dose of 2 mg/kg of 6, an antiaggregating effect was still observed at 24 h (44 +/- 12% inhibition, P < 0.05). 6 was well tolerated in animals, showing that, on the basis of these studies, it is a suitable candidate for development as an orally active antithrombotic agent.

SR 121787, a new orally active fibrinogen receptor antagonist.

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 microM. 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 microg/kg, and eight hours after the administration of 100 microg/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 microg/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.