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,...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-08, Vol.37 (16), p.2537-2551
Main Authors: Egbertson, Melissa S, Chang, Charles T.-C, Duggan, Mark E, Gould, Robert J, Halczenko, Wasyl, Hartman, George D, Laswell, William L, Lynch, Joseph J, Lynch, Robert J
Format: Article
Language:English
Subjects:
Adenosine Diphosphate - pharmacology
Amino Acid Sequence
Animals
Dogs
Endothelium, Vascular - drug effects
Endothelium, Vascular - physiology
Humans
Kinetics
Models, Molecular
Molecular Sequence Data
Molecular Structure
Oligopeptides - pharmacology
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - chemical synthesis
Platelet Aggregation Inhibitors - pharmacology
Platelet Membrane Glycoproteins - antagonists & inhibitors
Structure-Activity Relationship
Templates, Genetic
Tirofiban
Tyrosine - analogs & derivatives
Tyrosine - chemical synthesis
Tyrosine - pharmacology
Umbilical Veins
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00042a007