SC-54684A - AN ORALLY-ACTIVE INHIBITOR OF PLATELET-AGGREGATION

Background Intravenous therapy has been shown to be beneficial in the prevention of acute platelet-associated thrombotic events. However, or ally active agents would be advantageous for chronic therapy. Fibrinog en receptor antagonists block the fibrinogen/platelet interaction and thus inhibit a step required for thrombus formation. To date, no orall y active fibrinogen binding inhibitors have been characterized. SC-546 84A, now in clinical trial, is the orally active prodrug of a potent a nd specific fibrinogen binding antagonist. Methods and Results We meas ured inhibition of I-125-fibrinogen binding to activated platelets and inhibition of aggregation in platelet-rich plasma to selected agonist s and showed IC(50)s of 1.0x10(-8) and 3 to 7x10(-8) mol/L, respective ly. Specificity of the active moiety was determined by studying its ef fect on the binding of (1) neutrophils to interleukin (IL)-1 beta-stim ulated endothelial cells, (2) endothelial cells to fibronectin, and (3 ) vitronectin to isolated vitronectin and fibrinogen receptors. No eff ect was observed on the binding neutrophils to IL-stimulated endotheli al cells or endothelial cell binding to fibronectin. There was a fivef old separation between binding to isolated receptors of vitronectin an d fibrinogen. Collagen-induced aggregation was inhibited by 80%, and b leeding time was increased approximate to 2.5-fold when the active moi ety was infused to steady state at 0.2 mu g/kg per minute in dogs. Whe n the ester prodrug was given orally and the active moiety was given i ntravenously, the oral systemic activity was approximate to 20%. Pharm acokinetic analysis after intravenous infusion of the prodrug or activ e moiety showed that the prodrug was rapidly converted to the active m oiety; 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%. Conclusions SC-54684A, an orally active antiplatelet drug now in clinical trial, is shown to be a potent, spe cific fibrinogen binding inhibitor that blocks platelet aggregation to a wide variety of known stimuli and has good bioavailability in anima ls.