Design and Evaluation of Nonpeptide Fibrinogen γ-Chain Based GPIIb/IIIa Antagonists

William J. Hoekstra, Mary Pat Beavers, Patricia Andrade-Gordon, Mary F. Evangelista, Patricia M. Keane, Jeffery B. Press, Karen A. Tomko, Francis Fan, Marek Kloczewiak, Kevin H Mayo, Kathleen A. Durkin, Dennis C. Liotta

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44 Scopus citations

Abstract

Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the γ-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most interesting compound from our study, RWJ 50042 (26), exhibits potent inhibition of fibrinogen binding to GPIIb/IIIa (IC50 = 0.009 μM), as well as thrombin- or collagen-induced platelet aggregation (IC50 = 0.76, 0.14 μM). Since the 400-411 sequence is required for γ-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-á-vis other RGD (Arg-Gly-Asp)-presenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor.

Original languageEnglish (US)
Pages (from-to)1582-1592
Number of pages11
JournalJournal of medicinal chemistry
Volume38
Issue number10
DOIs
StatePublished - May 1 1995

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