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(Circulation. 1995;91:403-410.)
© 1995 American Heart Association, Inc.

Articles

SC-54684A: An Orally Active Inhibitor of Platelet Aggregation

Nancy S. Nicholson, MBA, MS; Susan G. Panzer-Knodle, BS; Anita K. Salyers, BS; Beatrice B. Taite, AA; James A. Szalony, MS; Neal F. Haas, BS; Lucy W. King, BS; Jeffery A. Zablocki, PhD; Bradley T. Keller, PhD; Kay Broschat, PhD; V. Wayne Engleman, MS; Marc Herin, PhD; Phillipe Jacqmin, PhD; Larry P. Feigen, PhD

From the Departments of Cardiovascular Diseases Research (N.S.N., S.G.P.-K., A.K.S., B.B.T., J.A.S., N.F.H., L.W.K., L.P.F.) and Chemical Research (J.A.Z.), Searle, Skokie, Ill; the Departments of Cardiovascular Diseases (B.T.K.) and Monsanto Corporate Research (K.B.), St Louis, Mo; Monsanto Corporate Research (W.E.), St Louis, Mo; the Department of Pharmacokinetics and Drug Metabolism (M.H.), Lilly Mont-Saint-Guibert Development Center, Mont St Guibert, Belgium; and Janssen Research Foundation (P.J.), Beerse, Belgium.

Correspondence to Nancy Nicholson, Searle, 4901 Searle Parkway, Skokie, IL 60077.

Background 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.

Methods and Results 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 1.0x10^-8 and 3 to 7x10^-8 mol/L, respectively. Specificity of the active moiety was determined by studying its effect on the binding of (1) neutrophils to interleukin (IL)-1ß–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 2.5-fold when the active moiety was infused to steady state at 0.2 µg/kg per minute in dogs. When the ester prodrug was given orally and the active moiety was given intravenously, the oral systemic activity was 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 t of 6.5 hours. When the prodrug was administered both orally and intravenously, the systemic availability of the active moiety was 62%.

Conclusions 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.

Key Words: platelets • platelet aggregation inhibitors • thrombosis

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