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, 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.


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 1.0 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%.


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.
Nicholson
N S
NS
Monsanto Corporate Research, St Louis, MO.
Panzer-Knodle
S G
SG
Salyers
A K
AK
Taite
B B
BB
Szalony
J A
JA
Haas
N F
NF
King
L W
LW
Zablocki
J A
JA
Keller
B T
BT
Broschat
K
K
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001550:Benzamidines; D001682:Biological Availability; D002250:Carbon Radioisotopes; D004285:Dogs; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011485:Protein Binding; D012680:Sensitivity and Specificity; D013927:Thrombosis / Q000188:drug therapy
D001549:Benzamides; D001550:Benzamidines; D002250:Carbon Radioisotopes; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D005340:Fibrinogen; C091295:xemilofiban