title: Cyclic RGD peptide analogues as antiplatelet antithrombotics.
abstract: 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).
authors.affiliation: Bioorganic Chemistry, Genentech, Inc., South San Francisco, California 94080.
authors.forename: P L
authors.initials: PL
authors.lastname: Barker
authors.forename: S
authors.initials: S
authors.lastname: Bullens
authors.forename: S
authors.initials: S
authors.lastname: Bunting
authors.forename: D J
authors.initials: DJ
authors.lastname: Burdick
authors.forename: K S
authors.initials: KS
authors.lastname: Chan
authors.forename: T
authors.initials: T
authors.lastname: Deisher
authors.forename: C
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: T R
authors.initials: TR
authors.lastname: Gadek
authors.forename: R
authors.initials: R
authors.lastname: Gantzos
authors.forename: M T
authors.initials: MT
authors.lastname: Lipari
mesh_terms: D000595:Amino Acid Sequence; D003500:Cyclization; D004797:Enzyme-Linked Immunosorbent Assay; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism; D018000:Receptors, Peptide; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D005343:Fibrinolytic Agents; D010455:Peptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D013454:Sulfoxides; C051382:arginyl-glycyl-aspartic acid directed cell adhesion receptor; C074915:G 4120