Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp.
Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation. Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of > 24,000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with i.v. infusions of 0.1-10 micrograms/kg/min of 23m in anesthetized dogs, with 10 micrograms/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infusions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.
Egbertson
M S
MS
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
Chang
C T
CT
Duggan
M E
ME
Gould
R J
RJ
Halczenko
W
W
Hartman
G D
GD
Laswell
W L
WL
Lynch
J J
JJ
Lynch
R J
RJ
Manno
P D
PD
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013698:Templates, Genetic; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014471:Umbilical Veins
D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D014443:Tyrosine; D000244:Adenosine Diphosphate; C047981:arginyl-glycyl-aspartic acid; D000077466:Tirofiban