Antiplatelet and antithrombotic activity of RWJ-53308, a novel orally active glycoprotein IIb/IIIa antagonist.
RWJ-53308 is a novel nonpeptide glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist that inhibits fibrinogen binding to GPIIb/IIIa with an IC(50) of 0.4+/-0.3 nM. RWJ-53308 inhibits thrombin-induced platelet aggregation in human gel-filtered platelets (IC(50)=60+/-12 nM) and platelet aggregation in human platelet-rich plasma (PRP) in response to collagen, arachidonic acid, ADP, and SFLLRN-NH(2) (IC(50)=60+/-10, 150+/-30, 70+/-4, and 160+/-80 nM, respectively). The potency of RWJ-53308 in dog and guinea pig PRP is similar to human PRP. RWJ-53308 inhibits ex vivo collagen- and ADP-induced platelet aggregation in conscious dogs for up to 4 h following 0.3 mg/kg iv, and through 4 and 6 h following 1 and 3 mg/kg po. Oral bioavailability is 16+/-7%. RWJ-53308 reduces thrombus weight in a canine arteriovenous (AV) shunt model following intravenous (0.01-0.1 mg/kg) and oral (3 mg/kg) administration. In a guinea pig carotid artery pinch-injury model, RWJ-53308 completely suppresses thrombus-induced cyclic flow reductions (CFR) at 0.7 mg/kg iv. RWJ-53308 also blocks thrombus formation in photoactivation- and ferric chloride-induced models of thrombosis in guinea pigs at 0.3 and 1 mg/kg iv, respectively. In summary, RWJ-53308 is a potent orally active GPIIb/IIIa antagonist that may be useful for both acute and chronic treatment of arterial thrombotic disorders.
Damiano
B P
BP
R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776, USA.
Mitchell
J A
JA
Giardino
E
E
Corcoran
T
T
Haertlein
B J
BJ
de Garavilla
L
L
Kauffman
J A
JA
Hoekstra
W J
WJ
Maryanoff
B E
BE
Andrade-Gordon
P
P
D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D013927:Thrombosis / Q000188:drug therapy
D009557:Nipecotic Acids; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011725:Pyridines; C402922:elarofiban; D005340:Fibrinogen