Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp.

Article Details

Citation

Egbertson MS, Chang CT, Duggan ME, Gould RJ, Halczenko W, Hartman GD, Laswell WL, Lynch JJ Jr, Lynch RJ, Manno PD, et al.

Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp.

J Med Chem. 1994 Aug 5;37(16):2537-51.

PubMed ID
8057299 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
TirofibanIntegrin beta-3IC 50 (nM)260000N/AN/ADetails
TirofibanIntegrin beta-3IC 50 (nM)9N/AN/ADetails
TirofibanIntegrin beta-3IC 50 (nM)62000N/AN/ADetails