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

作者：Gábor A. G. Sulyok, Christoph Gibson, Simon L. Goodman, Günter Hölzemann, Matthias Wiesner, Horst Kessler · 发表于：Journal of Medicinal Chemistry · 年份：2001 · DOI：10.1021/jm0004953 · 被引用次数：100 · 研究领域：Cell Adhesion Molecules Research、Monoclonal and Polyclonal Antibodies Research、Platelet Disorders and Treatments

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.