ABSTRACT
A novel class of dehydro-ß-proline-containing peptidomimetics, designed to be effective as α4ß1 integrin ligands, has been developed on the basis of the fundamental requirements for the interactions of these transmembrane receptors with bioactive ligands. Dehydro-ß-proline ring has been synthesized through an original pathway, involving ring closing metathesis of a diallylamino derivative. The synthesized products showed to be effective and selective as α4ß1 integrin antagonists and displayed IC50 values in the nanomolar range in cell adhesion inhibition assays and in VCAM-1-induced phosphorylation of extracellular-signal-regulated kinases. Significant activity was observed also toward the homologous integrin α4ß7, while they did not display any activity toward selected members of ß1, ß2, and ß3 families. A strong dependence on the stereochemistry of the heterocyclic central core could be observed. The great importance of α4ß1 integrin in chronic inflammatory and autoimmune diseases suggests a possible exploitation of these ligands as lead compounds for therapeutic tools development.
ABSTRACT
A novel class of low molecular weight ligands of αvß3 and α5ß1 integrins, that possess a dehydro-ß-amino acid as conformationally constrained core, linked to the pharmacophoric moieties mimicking the RGD recognition sequence, have been synthesized through a very simple protocol. Cell adhesion assays and integrin-mediated signaling activation experiments suggested a good affinity of these compounds toward both integrin receptors. Moreover, further elongation with two glycine units allowed to obtain an excellent dual inhibitor. Structural models for αvß3 integrin-ligand binding confirmed that the dehydro-ß-amino derivatives are able to act as an electrostatic clamp by establishing several stabilizing interactions with the receptor.
