SKF-106760

The in vivo pharmacol. profile of SK&F 106760 [N^α-acetylcyclo(S,S)-cysteinyl-N^α-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated.In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 μg/mL) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., resp.Plasma levels of SK&F 106760 were measured by high-performance liquid chromatog. after i.v. bolus administration of 1 mg/kg.An initial α-disposition phase with a T_1/2 of 11 ± 6 min was followed by a longer terminal β-elimination phase with a T_1/2 of 66 ± 12 min, which accounted for 79 ± 9% of the total area under the plasma concentration-time curve.The apparent steady-state volume of distribution was 259 ± 26 mL/kg and the plasma clearance was 3.4 ± 0.8 mL/min/kg.The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 ± 52 nM.After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%.In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.Furthermore, at a dose of 3.0 mg/kg i.v., SK&F 106760 produced a 78% reduction in the incidence of fibrin/platelet-dependent coronary artery thrombosis.At 0.3 to 3.0 mg/kg i.v., SK&F 106760 produced a dose-related enhancement in the thrombolytic efficacy of streptokinase in anesthetized dogs, by reducing the time to reperfusion and inhibiting reocclusion.However, SK&F 106760 (100 μM) did not potentiate streptokinase-mediated canine clot lysis in vitro, indicating that SK&F 106760 has no direct effect on the intrinsic fibrinolytic activity of streptokinase.Thus, SK&F 106760 is a potent antithrombotic agent in vivo capable of inhibiting both platelet- and fibrin/platelet-dependent coronary artery thrombosis and enhancing the thrombolytic efficacy of streptokinase at doses that inhibit ex vivo platelet aggregation.

The properties of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methyl-arginyl-glycyl-aspartyl-penicillamine-amide] as a GPIIb/IIIa antagonist have been studied in vitro and compared with those of the parent molecule, Ac-RGDS-NH2. Ac-RGDS-NH2 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 530 +/- 73 nM. In canine platelet rich plasma Ac-RGDS-NH2 produced a concentration related inhibition of adenosine diphosphate-induced platelet aggregation following preincubation for 3 min with an IC50 of 91 +/- 1 microM. However, incubation in platelet rich plasma for 3 hr abolished the activity of Ac-RGDS-NH2. SK&F 106760 inhibited biotinylated fibrinogen binding to purified human GPIIb/IIIa immobilized on plastic microtitre plates with a Ki of 477 +/- 57 pM. SK&F 106760 inhibited adenosine diphosphate-induced platelet aggregation in human platelet rich plasma with an IC50 of 230 +/- 60 nM but did not inhibit the von Willebrand Factor receptor (GPIb/IX)-mediated platelet agglutination produced by ristocetin. In canine platelet rich plasma SK&F 106760 inhibited aggregation produced by adenosine diphosphate, collagen and epinephrine/U-46619 with IC50 values of 355 +/- 35, 260 +/- 20, and 490 +/- 90 nM, respectively and in gel filtered platelets inhibited thrombin-mediated aggregation with an IC50 of 188 +/- 10 nM. Preincubation of SK&F 106760 in platelet rich plasma for three hours had no significant effect on its ability to inhibit adenosine diphosphate-induced platelet aggregation. SK&F 106760 produced insurmountable inhibition of adenosine diphosphate-induced platelet aggregation in the presence of constant fibrinogen concentrations, but produced competitive inhibition of the concentration-response curve to fibrinogen in adenosine diphosphate-activated platelets with a Kb of 8.0 +/- 1.0 nM. Thus, SK&F 106760 is a potent, stable competitive GPIIb/IIIa antagonist with no detectable activity at the von Willebrand Factor receptor (GPIb/IX).