SC-54684A : an orally active inhibitor of platelet aggregation

• Published in: Circulation (New York, N.Y.) N.Y.), 1995-01, Vol.91 (2), p.403-410
• Main Authors: NICHOLSON, N. S, PANZER-KNODLE, S. G, ENGLEMAN, V. W, HERIN, M, JACQMIN, P, FEIGEN, L. P, SALYERS, A. K, TAITE, B. B, SZALONY, J. A, HAAS, N. F, KING, L. W, ZABLOCKI, J. A, KELLER, B. T, BROSCHAT, K
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Benzamides - pharmacokinetics; Benzamidines; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Carbon Radioisotopes; Dogs; Fibrinogen - metabolism; Humans; Medical sciences; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Platelet Membrane Glycoproteins - physiology; Protein Binding; Sensitivity and Specificity; Thrombosis - drug therapy
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.91.2.403

Intravenous therapy has been shown to be beneficial in the prevention of acute platelet-associated thrombotic events. However, orally active agents would be advantageous for chronic therapy. Fibrinogen receptor antagonists block the fibrinogen/platelet interaction and thus inhibit a step required for thrombus formation. To date, no orally active fibrinogen binding inhibitors have been characterized. SC-54684A, now in clinical trial, is the orally active prodrug of a potent and specific fibrinogen binding antagonist. We measured inhibition of 125I-fibrinogen binding to activated platelets and inhibition of aggregation in platelet-rich plasma to selected agonists and showed IC50s of 1.0 x 10(-8) and 3 to 7 x 10(-8) mol/L, respectively. Specificity of the active moiety was determined by studying its effect on the binding of (1) neutrophils to interleukin (IL)-1 beta-stimulated endothelial cells, (2) endothelial cells to fibronectin, and (3) vitronectin to isolated vitronectin and fibrinogen receptors. No effect was observed on the binding neutrophils to IL-stimulated endothelial cells or endothelial cell binding to fibronectin. There was a fivefold separation between binding to isolated receptors of vitronectin and fibrinogen. Collagen-induced aggregation was inhibited by 80%, and bleeding time was increased approximately 2.5-fold when the active moiety was infused to steady state at 0.2 micrograms/kg per minute in dogs. When the ester prodrug was given orally and the active moiety was given intravenously, the oral systemic activity was approximately 20%. Pharmacokinetic analysis after intravenous infusion of the prodrug or active moiety showed that the prodrug was rapidly converted to the active moiety; the active moiety had a t1/2 of 6.5 hours. When the prodrug was administered both orally and intravenously, the systemic availability of the active moiety was 62%. SC-54684A, an orally active antiplatelet drug now in clinical trial, is shown to be a potent, specific fibrinogen binding inhibitor that blocks platelet aggregation to a wide variety of known stimuli and has good bioavailability in animals.