Cyclic RGD peptide analogues as antiplatelet antithrombotics

J Med Chem. 1992 May 29;35(11):2040-8. doi: 10.1021/jm00089a014.


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).

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Cyclization
  • Enzyme-Linked Immunosorbent Assay
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology
  • Humans
  • Molecular Conformation
  • Molecular Sequence Data
  • Molecular Structure
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Peptides / pharmacology
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis*
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Membrane Glycoproteins / metabolism
  • Receptors, Immunologic / chemistry*
  • Receptors, Immunologic / metabolism
  • Receptors, Peptide*
  • Structure-Activity Relationship
  • Sulfoxides / chemical synthesis*
  • Sulfoxides / chemistry
  • Sulfoxides / pharmacology
  • X-Ray Diffraction


  • Fibrinolytic Agents
  • Peptides
  • Peptides, Cyclic
  • Platelet Aggregation Inhibitors
  • Platelet Membrane Glycoproteins
  • Receptors, Immunologic
  • Receptors, Peptide
  • Sulfoxides
  • arginyl-glycyl-aspartic acid directed cell adhesion receptor
  • G 4120