title: Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists.
abstract: The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Sall
authors.forename: A E
authors.initials: AE
authors.lastname: Arfsten
authors.forename: J A
authors.initials: JA
authors.lastname: Bastian
authors.forename: M L
authors.initials: ML
authors.lastname: Denney
authors.forename: C S
authors.initials: CS
authors.lastname: Harms
authors.forename: J R
authors.initials: JR
authors.lastname: McCowan
authors.forename: J M
authors.initials: JM
authors.lastname: Morin
authors.forename: J W
authors.initials: JW
authors.lastname: Rose
authors.forename: R M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: M S
authors.initials: MS
authors.lastname: Smyth
authors.forename: S L
authors.initials: SL
authors.lastname: Um
authors.forename: B G
authors.initials: BG
authors.lastname: Utterback
authors.forename: R T
authors.initials: RT
authors.lastname: Vasileff
authors.forename: J H
authors.initials: JH
authors.lastname: Wikel
authors.forename: V L
authors.initials: VL
authors.lastname: Wyss
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
mesh_terms: D001120:Arginine; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001550:Benzamidines; D007202:Indicators and Reagents; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen; D001120:Arginine