SR 121787, a New Orally Active Fibrinogen Receptor Antagonist

Abstract

SummaryThe 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.

SM-20302, a Nonpeptide GPIIb/IIIa Receptor Antagonist, Exhibits a Wide Therapeutic Window in a Newly Developed Hemorrhage Model in Mice*

“…We first studied the antiaggregatory effect (IC 50 ) of SM-20302 in vitro. SM-20302 showed a potent inhibition of platelet aggregation in human PRP and its effect was independent of various agonists examined (Table 1), in accordance with other low-molecular-weight GPIIb/ IIIa inhibitors reported (39)(40)(41)(42). In contrast, the interaction of platelets with vWF via GPIb/IX was not blocked by SM-20302 since it failed to inhibit the agglutination response to ristocetin.…”

Ex vivo?in vitro interaction between aspirin, clopidogrel, and the glycoprotein IIb/IIIa inhibitors abciximab and SR121566A

“…The effect on fibrinogen binding has been quantified as the difference between unstimulated platelets and binding after platelet activation by TRAP. Concentrations of the GPIIb/IIIa inhibitors correspond to their ED 25 to ED 50 for fibrinogen binding, as assessed in a pilot study 15 and supported by reference data on effective plasma concentrations of abciximab 20 and SR121566A 7 . However, 80% inhibition of fibrinogen binding is suggested for abciximab as a target range during coronary interventions or unstable angina, 21 whereas for long‐term therapy with oral agents (such as SR121566A), a lower grade of inhibition is suggested to avoid bleeding complications 21 , 22 …”

“…Afterward, the thienopyridine is used for approximately 1 month in addition to aspirin. Oral GPIIb/IIIa‐blockers such as the peptidomimetic compound SR121566A (the active form of its orally available pro‐drug) 7 have been developed for long‐term treatment and may be given together with aspirin and, in the case of aspirin intolerance, together with a thienopyridine 5 , 8 . Therefore the pharmacodynamic interaction of these antiplatelet drugs deserves attention 8 , 9 .…”

Studies on the Binding of 3H-SR121566, an Inhibitor of Gp IIb-IIIa Activation

“…We have determined the binding characteristics of SR121566, an antagonist of the Gp IIb-IIIa complex (16), its interactions with this complex and its functionality on whole platelets. In our experiments, 3 H-SR121566 specifically bound to cells expressing the Gp IIb-IIIa complex (platelets and megakarioblastic cell lines), whereas no binding was observed in cells expressing Gp IIIa associated with another alpha subunit (HUVEC, hSMC and MRC5) or with erythrocytes which do not express integrins.…”

“…SR121566 is a potent Gp IIb-IIIa antagonist developed as an antithrombotic drug (15). In vitro, SR121566 has been shown to specifically inhibit the adhesion of platelets to fibrinogen and their aggregation induced by various agonists (16). In vivo, SR121566 displayed a strong and sustained antiaggregating activity in monkeys, dogs, guinea pigs and rabbits, associated with a potent antithrombotic effect in several models (17).…”