EXTENDED INHIBITION OF PLATELET-AGGREGATION WITH THE ORALLY-ACTIVE PLATELET INHIBITOR SC-54684A

Background Platelet aggregation is important in thrombotic events, and platelets play a major role in the etiology of several cardiovascular diseases. Platelet aggregation requires the binding of fibrinogen (fg n) to activated platelets. Synthetic peptides modeled after the RGD bi nding sequence on the fgn alpha-chain block the platelet glycoprotein (GP) IIb/IIIa receptor for fgn and effectively inhibit aggregation. SC -54684A (SCp, orally active prodrug of the active moiety SC-54701, SCa ) is a mimetic of the RGD-containing peptide sequence that is recogniz ed by the platelet GPIIb/IIIa receptor. SCa blocks the binding of fgn to the platelet and therefore prevents platelet aggregation in respons e to all agonists. Methods and Results SCp was administered orally at 1.25, 2.5, 5.0, and 7.5 mg/kg in a single-dose, dose-ranging study. Bl ood samples were taken periodically for 24 hours, and platelet-rich pl asma was prepared and tested for inhibition of ex vivo collagen-induce d platelet aggregation. The plasma concentration of active moiety was determined by bioassay. The time, inhibition, and concentration data w ere used to predict two doses that would result in minimum daily inhib ition levels of 30% and 70% when administered twice daily (0.6 and 2.4 mg/kg, respectively). SCp was administered orally to conscious dogs t wice daily for 14 days (after dose adjustment). Blood samples were obt ained at daily peak and trough plasma levels (predicted from dose-rang ing study). Inhibition of ex vive collagen-induced platelet aggregatio n and concentration of active moiety in the plasma were determined. Av erage inhibition of platelet aggregation and plasma concentration of a ctive moiety amounted to approximately 21% and 14 ng/mL at 1.5 mg/kg B ID and 75% and 24 ng/mL at 2.4 mg/kg BID at daily minimum plasma level s (trough) in steady state. Platelet counts in the 2.4-mg/kg group dec lined from 3.2x10(5)/mu L to 2.5x10(5)/mu L in the first 9 days of dos ing, with no further decline despite continued administration of compo und. No changes were observed in the animals receiving 1.5 mg/kg. Conc lusions The results of the dose-ranging study show that oral administr ation of SCp results in dose-dependent inhibition of platelet aggregat ion. As shown in the 14-day administration, this dose-dependent inhibi tion can be maintained for an extended period while exhibiting no adve rse effects. SCp is a leading candidate for development and is current ly in clinical trials.