The in vitro pharmacological profile of SK&F 106760, a novel GPIIB/IIIA antagonist.
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).
SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
A J
AJ
Nichols
J A
JA
Vasko
R E
RE
Valocik
L J
LJ
Kopaciewicz
B L
BL
Storer
F E
FE
Ali
T
T
Romoff
R
R
Calvo
J M
JM
Samanen
D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010979:Platelet Function Tests; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding
D009842:Oligopeptides; D010456:Peptides, Cyclic; D010980:Platelet Membrane Glycoproteins; C060414:acetyl-arginyl-glycyl-aspartyl-serinamide; C071275:SK&F 106760