Dehydro-beta-proline Containing Alpha-4-beta-1 Integrin Antagonists: Stereochemical Recognition in Ligand-Receptor Interplay

A novel class of dehydro-b-proline-contg. peptidomimetics, designed to be effective as a4b1 integrin ligands, has been developed on the basis of the fundamental requirements for the interactions of these transmembrane receptors with bioactive ligands. Dehydro-b-proline ring has been synthesized through an original pathway, involving ring closing metathesis of a diallylamino deriv. The synthesized products showed to be effective and selective as a4b1 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 obsd. also toward the homologous integrin a4b7, while they did not display any activity toward selected members of b1, b2, and b3 families. A strong dependence on the stereochem. of the heterocyclic central core could be obsd. The great importance of a4b1 integrin in chronic inflammatory and autoimmune diseases suggests a possible exploitation of these ligands as lead compds. for therapeutic tools development.