title: Solid-phase synthesis of a nonpeptide RGD mimetic library: new selective alphavbeta3 integrin antagonists.
abstract: The solid-phase synthesis of a low molecular weight RGD mimetic library is described. Activities of the compounds in inhibiting the interaction of ligands, vitronectin and fibrinogen, with isolated immobilized integrins alphavbeta3 and alphaIIbbeta3 were determined in a screening assay. Highly active and selective nonpeptide alphavbeta3 integrin antagonists with regard to orally bioavailability were developed, based on the aza-glycine containing lead compound 1. An important variation is the substitution of the aspartic amide of 1 by an aromatic residue. Furthermore, different guanidine mimetics have been incorporated to improve the pharmacokinetic profile. Exchange of the beta-amino acid NH by a methylene moiety in one set of RGD mimetics leads to the azacarba analogue compounds representing a novel peptidomimetic approach, which should increase the metabolic stability.
authors.affiliation: Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: G A
authors.initials: GA
authors.lastname: Sulyok
authors.forename: C
authors.initials: C
authors.lastname: Gibson
authors.forename: S L
authors.initials: SL
authors.lastname: Goodman
authors.forename: G
authors.initials: G
authors.lastname: Hölzemann
authors.forename: M
authors.initials: M
authors.lastname: Wiesner
authors.forename: H
authors.initials: H
authors.lastname: Kessler
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D019992:Databases as Topic; D005340:Fibrinogen / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019096:Vitronectin / Q000037:antagonists & inhibitors
chemical_list: D000578:Amidines; D006146:Guanidines; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011725:Pyridines; D019030:Receptors, Vitronectin; D019096:Vitronectin; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen