Synthesis and Structure−Activity Relationship of Mannose-Based Peptidomimetics Selectively Blocking Integrin α4β7 Binding to Mucosal Addressin Cell Adhesion Molecule-1

• Published in: Journal of medicinal chemistry 2003-12, Vol.46 (26), p.5752-5762
• Main Authors: Locardi, Elsa, Boer, Jürgen, Modlinger, Armin, Schuster, Anja, Holzmann, Bernhard, Kessler, Horst
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020487h

As part of our ongoing research in the development of α4β7 integrin antagonists, we are interested in peptidomimetics based on a rigid scaffold to allow the display of essential side chains in a suitable binding conformation while eliminating backbone amide bonds and therefore improving pharmacokinetic parameters of the drug. Except for a few examples, peptidomimetics scaffolds have only been moderately successful and often yield molecules that lack the potency of their peptide counterparts. However, we present herein a successful application of using a rigid scaffold. Starting from a mannopyranoside analogue previously discovered in our laboratory as an inhibitor of the α4β1/vascular cell adhesion molecule interaction, a biased library of functionalized carbohydrates was developed. One compound emerged from this library as an active and selective antagonist toward the α4β7/mucosal addressin cell adhesion molecule interaction. Conformational implications and the relevance of different pharmacophoric patterns will be discussed in order to explain the reverse selectivity and enhanced affinity.