In vitro and in vivo effects of a peptide mimetic (SC-47643) of RGD as an antiplatelet and antithrombotic agent.
Platelet aggregation requires binding of fibrinogen (fgn) to activated platelets and inhibition of this binding blocks platelet aggregation. Synthetic peptides modeled after the platelet binding sequence on fgn block the platelet glycoprotein IIb/IIIa receptor and effectively inhibit aggregation. SC-47643 (SC) is a mimetic of the RGD-containing peptide sequence that is recognized by the platelet IIb/IIIa receptor. SC inhibited fgn binding to activated platelets (IC50: 1.0 x 10(-5) M) and prevented platelet aggregation in response to a variety of platelet agonists in both washed human platelets and platelet rich plasma (IC50's ranging from 4 x 10(-6) to 1 x 10(-5) M, respectively). SC inhibited collagen induced thrombocytopenia in the rat (ED50 0.07 mg/kg and t1/2 36 min). In dogs ex vivo collagen induced platelet aggregation was inhibited 50% after a bolus injection of 1.7 mg/kg. After a steady state infusion (2 hr), the ED50 was 0.03 mg/kg/min, with no effects on blood pressure, heart rate or platelet count. These data demonstrate that SC, a peptide mimetic of the natural fgn binding sequence, is capable of blocking platelet-fgn interactions and platelet aggregation.
Nicholson
N S
NS
Cardiovascular Diseases Research, G.D. Searle, Skokie, IL 60077.
Panzer-Knodle
S G
SG
Salyers
A K
AK
Taite
B B
BB
King
L W
LW
Miyano
M
M
Gorczynski
R J
RJ
Williams
M H
MH
Zupec
M E
ME
Tjoeng
F S
FS
D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism; D005343:Fibrinolytic Agents; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D051381:Rats; D013921:Thrombocytopenia / Q000517:prevention & control
D005343:Fibrinolytic Agents; D006146:Guanidines; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; C070872:8-guanidinooctanoyl-Asp-2-(4-methoxyphenyl)ethylamide; D001224:Aspartic Acid; D005340:Fibrinogen