THE IN-VITRO PHARMACOLOGICAL PROFILE OF SK-AND-F-106760, A NOVEL GPIIB IIIA ANTAGONIST/

The properties of SK&F 106760 methylarginyl-glycyl-aspartyl-penicillam ine-amide] as a GPIIb/IIIa antagonist have been studies in vitro and c ompared with those of the parent molecule, Ac-RGDS-NH2. Ac-RGDS-NH2 in hibited biotinylated fibrinogen binding to purified human GPIIb/IIIa i mmobilized on plastic microtitre plates with a K-i of 530 +/- 73 nM. I n canine platelet rich plasma Ac-RGDS-NH2 produced a concentration rel ated inhibition of adenosine diphosphate-induced platelet aggregation following preincubation for 3 min with an IC50 of 91 +/- 1 mu M. Howev er, 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 K-i of 477 +/- 57 pM. SK&F 106760 inhibited adenosine diphosph ate-induced platelet aggregation in human platelet rich plasma with an IC50 of 230 +/- 60 nM but did not inhibit the von Willebrand Factor r eceptor (GPIb/IX)-mediated platelet agglutination produced by ristocet in. In canine platelet rich plasma SK&F 106760 inhibited aggregation p roduced by adenosine diphosphate, collagen and epinephrine/U-46619 wit h IC50 values of 355 +/- 35, 260 +/- 20, and 490 +/- 90 nM, respective ly and in gel filtered platelets inhibited thrombin-mediated aggregati on with an IC50 of 188 +/- 10 nM. Preincubation of SK&F 106760 produce d insurmountable inhibition of adenosine diphosphate-induced platelet aggregation in the presence of constant fibrinogen concentrations, but produced competitive inhibition of the concentration-response curve t o fibrinogen in adenosine diphosphate-activated platelets with a K-b o f 8.0 +/- 1.0 nM. Thus, SK&F 106760 is a potent, stable competitive GP IIb/IIIa antagonist with no detectable activity at the von Willebrand Factor receptor (GPIb/IX).