Novel thiazole-based heterocycles as selective inhibitors of fibrinogen-mediated platelet aggregation.
The synthesis and biological activity of novel thiazole-based heterocycles as inhibitors of thrombin-induced human platelet aggregation are described. Further evaluation of selected compounds show they inhibit platelet aggregation as stimulated by a variety of agonists. The more active compounds also were found to inhibit fibrinogen binding to platelets. To further delineate the mechanism of action of these compounds, direct binding studies with the purified glycoprotein (GP) IIb/IIIa receptor were performed. Flow cytometry analyses of 24 and 32 indicate that these compounds block the activation process of the GPIIb/IIIa receptor without denaturing the integrin receptor. On the basis of these studies, 32 exhibited the best profile as a novel nonpeptide inhibitor of fibrinogen-mediated platelet aggregation.
Drug Discovery Division, R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477.
P J
PJ
Sanfilippo
M J
MJ
Urbanski
K N
KN
Beers
A
A
Eckardt
R
R
Falotico
M H
MH
Ginsberg
S
S
Offord
J B
JB
Press
J
J
Tighe
K
K
Tomko
D005340:Fibrinogen / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology
D007457:Iodine Radioisotopes; D010975:Platelet Aggregation Inhibitors; D013844:Thiazoles; D005340:Fibrinogen; D013917:Thrombin