Pharmacological profile of G619, a new platelet aggregation inhibitor.
G619, a 4-OH-isophthalic acid derivative, was studied for its capacity to inhibit platelet aggregation. G619 dose-dependently inhibited U46619, collagen, ADP, PAF, thrombin and epinephrine-induced platelet aggregation in vitro. The IC50 values for inhibition of U46619-induced human and rabbit platelet aggregation were 39 and 43 microM, respectively. G619, at 100 microM, inhibited high concentration collagen (10 micrograms/ml)-induced aggregation of rabbit platelets pretreated with indomethacin and increased the level of cAMP in washed rabbit platelets by 30% (p less than 0.01 vs basal). However, G619, did not inhibit fibrinogen binding to GPIIb/IIIa receptor, phosphodiesterase, U46619-induced contractile responses on canine saphenous vein or rabbit aorta, calcium-induced vasoconstriction and thrombin or PAF-induced elevation of [Ca++]i in platelets in vitro. In vivo, the U46619-induced maximal thrombocytopenia in rats was reduced from 40% (vehicle) to 22% and 18% by 10 and 30 mg/kg of G619 i.v., respectively. G619 (30 mg/kg) had no effect on the U46619-induced vasopressor response or sudden death in rats, and had no effect on TxB2 formation. Our results indicate that G619 is a broad-spectrum platelet aggregation inhibitor and may have its effect on a common mechanism for platelet aggregation besides an effect on the thromboxane A2 receptor.
Yue
T L
TL
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Smith
E F
EF
Ohlstein
E H
EH
Sulpizio
A
A
Slivjak
M J
MJ
Rabinovici
R
R
Sellers
T S
TS
Lynch
K M
KM
Poyser
R
R
Feuerstein
G
G
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D003094:Collagen / Q000037:antagonists & inhibitors; D004285:Dogs; D004837:Epinephrine / Q000037:antagonists & inhibitors; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008297:Male; D010648:Phenylacetates / Q000494:pharmacology; D010847:Picolines / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012772:Shock, Septic / Q000097:blood; D013449:Sulfonamides / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000096:biosynthesis; D014661:Vasoconstriction / Q000187:drug effects
D001549:Benzamides; D010648:Phenylacetates; D010847:Picolines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D013449:Sulfonamides; C074732:3-carbamyl-(3'-picolyl)-4-methoxy-1-benzamide; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D003094:Collagen; D013917:Thrombin; C051762:daltroban; D002118:Calcium; D004837:Epinephrine