• DOI:10.1021/JM00089A014
• Corpus ID: 39953733

Cyclic RGD peptide analogues as antiplatelet antithrombotics.

@article{Barker1992CyclicRP,
  title={Cyclic RGD peptide analogues as antiplatelet antithrombotics.},
  author={Peter L. Barker and Sherron L. Bullens and Stuart Bunting and Daniel J Burdick and K S Chan and Theresa A. Deisher and Charles Eigenbrot and Thomas R. Gadek and Robin D. Gantzos and Michael T. Lipari},
  journal={Journal of medicinal chemistry},
  year={1992},
  volume={35 11},
  pages={
          2040-8
        }
}

• P. Barker, S. Bullens, +7 authors M. T. Lipari
• Published 29 May 1992
• Chemistry, Biology
• Journal of medicinal chemistry

Stimulation of platelets activates GPIIbIIIa, the heterodimeric integrin receptor, to bind fibrinogen (Fg), which results in platelet aggregation. GPIIbIIIa/Fg binding inhibitors are potentially suitable for acute use during and after thrombolytic therapy as antithrombotic agents. Incorporation of the tripeptide sequence Arg-Gly-Asp (RGD), a common structural element of many integrin ligands, into cyclic peptides produced a series of peptides of the general structure BrAc-(AA1)-RGD-Cys-OH, which were prepared by solid-phase peptide synthesis. Cyclization was accomplished by reaction of the N-terminal bromoacetyl group with the cysteine sulfhydryl at pH 8 at high dilution, resulting in thioether-bridged cyclic peptides [cyclo-S-Ac-(AA1)-RGD-Cys-OH]. Use of alpha-substituted bromoacetyl groups gave rise to an analogous series of acetyl-substituted thioether-bridged cyclic peptides. Oxidation of the thioethers produced separable diastereomeric sulfoxide-bridged cyclic peptides. After thorough evaluation in a GPIIbIIIa ELISA assay and a platelet aggregation assay, G-4120 (70A; AA1 = D-Tyr; sulfoxide bridge) was selected for further investigation as an antithrombotic agent. G-4120 was equipotent in the platelet aggregation assay to kistrin, a highly potent inhibitor of fibrinogen-mediated platelet aggregation isolated from snake venom (IC50 = 0.15 microM).