title: Design and evaluation of nonpeptide fibrinogen gamma-chain based GPIIb/IIIa antagonists.
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.
authors.affiliation: R. W. Johnson Pharmaceutical Research Institute, Pennsylvania 19477, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Hoekstra
authors.forename: M P
authors.initials: MP
authors.lastname: Beavers
authors.forename: P
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: M F
authors.initials: MF
authors.lastname: Evangelisto
authors.forename: P M
authors.initials: PM
authors.lastname: Keane
authors.forename: J B
authors.initials: JB
authors.lastname: Press
authors.forename: K A
authors.initials: KA
authors.lastname: Tomko
authors.forename: F
authors.initials: F
authors.lastname: Fan
authors.forename: M
authors.initials: M
authors.lastname: Kloczewiak
authors.forename: K H
authors.initials: KH
authors.lastname: Mayo
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D005340:Fibrinogen / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*
chemical_list: D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D005340:Fibrinogen