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

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.