NEW ORALLY-ACTIVE NONPEPTIDE FIBRINOGEN RECEPTOR (GPIIB-IIIA) ANTAGONISTS - IDENTIFICATION OF ETHYL THOXYCARBONYL)METHYL]PIPERID-4-YL]AMINO]PROPIONATE (SR-121787) AS A POTENT AND LONG-ACTING ANTITHROMBOTIC AGENT

The platelet fibrinogen receptor GpIIb-IIIa is curently considered a t arget of choice for drugs used in the prevention and treatment of thro mbosis. Ethyl -yl]-N-[(ethoxycarbonyl)methyl]piperid-4-yl]amino] propi onate (6, SR 121787) is a new antiaggregating agent which generates in vivo the corresponding diacid 19d (SR 121566), a non-peptide GpIIb-II Ia antagonist. In vitro, 19d inhibited ADP-induced aggregation of huma n and baboon platelets (IC50 46 +/- 11 and 54 +/- 6 nM, respectively), and on human platelets, 19d antagonized the binding of I-125-labeled fibrinogen (IC50 = 19.2 +/- 6.2 nM). Ex vivo, 8 h after an iv administ ration of 19d (100 mu g/kg, iv) to baboons, ADP-induced aggregation wa s strongly inhibited (more than 90%). At 8 h, the ED50 value was 24 +/ - 3.3 mu g/kg), and even 24 h after the administration of a single dos e of 100 mu g/kg of 19d, platelet aggregation was still significantly inhibited (50 +/- 6% inhibition, P < 0.05). In the same species, the o ral administration of 500 mu g/kg of 6 produced a nearly complete inhi bition of aggregation for up to 8 h (ED50 at 8 h was 193 +/- 20 mu g/k g). 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 t olerated in animals, showing that, on the basis of these studies, it i s a suitable candidate for development as an orally active antithrombo tic agent.