Document Report Card

ID: ALA1128350

Journal: J Med Chem

Title: Design and evaluation of nonpeptide fibrinogen gamma-chain based GPIIb/IIIa antagonists.

Authors: Hoekstra WJ, Beavers MP, Andrade-Gordon P, Evangelisto MF, Keane PM, Press JB, Tomko KA, Fan F, Kloczewiak M, Mayo KH.

Abstract: Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the gamma-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 (25), exhibits potent inhibition of fibrinogen binding to GPIIb/IIIa (IC50 = 0.009 microM), as well as thrombin- or collagen-induced platelet aggregation (IC50 = 0.76, 0.14 microM). Since the 400-411 sequence is required for gamma-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-a-vis other RGD (Arg-Gly-Asp)-presenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor.

CiteXplore: 7752183

DOI: 10.1021/jm00010a002