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 (fgn) to activated platelets. Synthetic peptides modeled after the RGD binding 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 recognized by the platelet GPIIb/IIIa receptor. SCa blocks the binding of fgn to the platelet and therefore prevents platelet aggregation in response to all agonists.


RESULTS
SCp was administered orally at 1.25, 2.5, 5.0, and 7.5 mg/kg in a single-dose, dose-ranging study. Blood samples were taken periodically for 24 hours, and platelet-rich plasma was prepared and tested for inhibition of ex vivo collagen-induced platelet aggregation. The plasma concentration of active moiety was determined by bioassay. The time, inhibition, and concentration data were used to predict two doses that would result in minimum daily inhibition levels of 30% and 70% when administered twice daily (0.6 and 2.4 mg/kg, respectively). SCp was administered orally to conscious dogs twice daily for 14 days (after dose adjustment). Blood samples were obtained at daily peak and trough plasma levels (predicted from dose-ranging study). Inhibition of ex vivo collagen-induced platelet aggregation and concentration of active moiety in the plasma were determined. Average inhibition of platelet aggregation and plasma concentration of active moiety amounted to approximately 21% and 14 ng/mL at 1.5 mg/kg BID and 75% and 24 ng/mL at 2.4 ng/kg BID at daily minimum plasma levels (trough) in steady state. Platelet counts in the 2.4-mg/kg group declined from 3.2 x 10(5)/microL to 2.5 x 10(5)/microL in the first 9 days of dosing, with no further decline despite continued administration of compound. No changes were observed in the animals receiving 1.5 mg/kg.


CONCLUSIONS
The results of the dose-ranging study show that oral administration of SCp results in dose-dependent inhibition of platelet aggregation. As shown in the 14-day administration, this dose-dependent inhibition can be maintained for an extended period while exhibiting no adverse effects. SCp is a leading candidate for development and is currently in clinical trials.
Szalony
J A
JA
Department of Cardiovascular Diseases, Searle, Skokie, Ill 60077.
Haas
N F
NF
Salyers
A K
AK
Taite
B B
BB
Nicholson
N S
NS
Mehrotra
D V
DV
Feigen
L P
LP
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001550:Benzamidines; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000502:physiology; D008099:Liver / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010976:Platelet Count
D001549:Benzamides; D001550:Benzamidines; D010975:Platelet Aggregation Inhibitors; C091295:xemilofiban