NONPEPTIDE GLYCOPROTEIN IIB IIIA INHIBITORS .17. DESIGN AND SYNTHESISOF ORALLY-ACTIVE, LONG-ACTING NONPEPTIDE FIBRINOGEN RECEPTOR ANTAGONISTS/

The synthesis and pharmacological evaluation of 5 (L-738,167), a poten t, selective non-peptide fibrinogen receptor antagonist is reported. C ompound 5 inhibited the aggregation of human gel-filtered platelets wi th an IC50 value of 8 nM and was found to be >33000-fold less effectiv e at inhibiting the attachment of human endothelial cells to fibrinoge n, fibronectin, and vitronectin than it was at inhibiting platelet agg regation. Ex vivo platelet aggregation was inhibited by >85% 24 h afte r the oral administration of 5 to dogs at 100 mu g/kg. The extended ph armacodynamic profile exhibited by 5 appears to be a consequence of it s high-affinity binding to GPIIb/IIIa on circulating platelets and sug gests that 5 is suitable for once-a-day dosing.