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Non-Peptide Glycoprotein IIb/IIIa Inhibitors. 17. Design and Synthesis of Orally Active, Long-Acting Non-Peptide Fibrinogen Receptor Antagonists

1997; American Chemical Society; Volume: 40; Issue: 12 Linguagem: Inglês

10.1021/jm9608117

1520-4804

Benny C. Askew, Rodney A. Bednar, Bohumil Bednář, David A. Claremon, Jacquelynn J. Cook, Charles McIntyre, Cecila A. Hunt, Robert J. Gould, Robert J. Lynch, Joseph J. Lynch, Stanley L. Gaul, Maria T. Stranieri, Gary R. Sitko, Marie A. Holahan, Joan D. Glass, Terrence Hamill, Lynn M. Gorham, Thomayant Prueksaritanont, John J. Baldwin, George D. Hartman,

Heparin-Induced Thrombocytopenia and Thrombosis

The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting the attachment of human endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by >85% 24 h after the oral administration of 5 to dogs at 100 μg/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.