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Non-peptide fibrinogen receptor antagonists. 7. Design and synthesis of a potent, orally active fibrinogen receptor antagonist



Non-peptide fibrinogen receptor antagonists. 7. Design and synthesis of a potent, orally active fibrinogen receptor antagonist



Journal of Medicinal Chemistry 38(17): 3332-3341



The design, synthesis, and pharmacological evaluation of L-734,217, a potent, low-molecular weight, orally active fibrinogen receptor antagonist, is reported. A strategy for producing low-molecular weight inhibitors from the peptide c-((Ac)CRGDC) A, previously reported from these laboratories, is outlined. This strategy combines a retrodesign analysis of the conformationally defined cyclic peptide A with stereochemical information present in the arginine-glycine-aspartic acid (RGD) tripeptide sequence, culminating with the discovery of L-734,217. L-734,217 inhibited the aggregation of human dog, and chimpanzee platelets at concentrations below 100 nM and was found to be gt 15000-fold less effective at inhibiting the attachment of human umbilical vein endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting the aggregation of platelets. L-734,217 showed significant ex vivo antiplatelet activity following oral administration in dogs and chimpanzees at doses of 1.0 and 2.0 mg/kg, respectively, and has been selected as a clinical candidate for development as an antithrombotic agent.

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Accession: 009103446

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PMID: 7650686

DOI: 10.1021/jm00017a017


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