Non-peptide glycoprotein IIb/IIIa inhibitors. 17. Design and synthesis of orally active, long-acting non-peptide fibrinogen receptor antagonists

  • J Med Chem. 1997 Jun 6;40(12):1779-88. doi: 10.1021/jm9608117.
B C Askew  1 ,  R A Bednar ,  B Bednar ,  D A Claremon ,  J J Cook ,  C J McIntyre ,  C A Hunt ,  R J Gould ,  R J Lynch ,  J J Lynch Jr ,  S L Gaul ,  M T Stranieri ,  G R Sitko ,  M A Holahan ,  J D Glass ,  T Hamill ,  L M Gorham ,  T Prueksaritanont ,  J J Baldwin ,  G D Hartman
Affiliations
  • 1. Merck Research Laboratories, Department of Medicinal Chemistry, West point, Pennsylvania 19486, USA.
PMID: 9191954 DOI: 10.1021/jm9608117
Abstract

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 micrograms/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.