Solid-Phase Synthesis of a Nonpeptide RGD Mimetic Library:  New Selective αvβ3 Integrin Antagonists

• Published in: Journal of medicinal chemistry Vol. 44; no. 12; pp. 1938 - 1950
• Main Authors: Sulyok, Gábor A. G, Gibson, Christoph, Goodman, Simon L, Hölzemann, Günter, Wiesner, Matthias, Kessler, Horst
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 07.06.2001
• Subjects: Biological and medical sciences; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Organic carbazate; Glycoprotein; Combinatorial chemistry; Non peptide compound; Vitronectin; Guanidines; Selectivity; In vitro; Integrin; Structure activity relation; Carboxylic acid; Chlorine Organic compounds; Chemical compound library; Benzenic compound; Antagonist; Solid phase; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0004953

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 αvβ3 and αIIbβ3 were determined in a screening assay. Highly active and selective nonpeptide αvβ3 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 β-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.