title: Non-peptide RGD surrogates which mimic a Gly-Asp beta-turn: potent antagonists of platelet glycoprotein IIb-IIIa.
abstract: Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp beta-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fisher
authors.forename: B
authors.initials: B
authors.lastname: Gunn
authors.forename: C S
authors.initials: CS
authors.lastname: Harms
authors.forename: A D
authors.initials: AD
authors.lastname: Kline
authors.forename: J T
authors.initials: JT
authors.lastname: Mullaney
authors.forename: A
authors.initials: A
authors.lastname: Nunes
authors.forename: R M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: A E
authors.initials: AE
authors.lastname: Arfsten
authors.forename: M A
authors.initials: MA
authors.lastname: Skelton
authors.forename: S L
authors.initials: SL
authors.lastname: Um
authors.forename: B G
authors.initials: BG
authors.lastname: Utterback
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
mesh_terms: D001224:Aspartic Acid; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005998:Glycine; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001224:Aspartic Acid; C047981:arginyl-glycyl-aspartic acid; D005998:Glycine