Shifting Towards αVβ6 Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

In recognition of the key role exerted by integrins in several life-threatening dysfunctions, the search for novel small-molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)-RGD based cyclopeptidomimetics with attracting α V β 3 integrin affinity and selectivity, the design and straightforward synthesis of eighteen new AmpRGD chemotypes bearing additional structural variants were herein implemented, to shift toward peptide-like α V β 6 integrin targeted binders. Hence, the ligand competence of the synthesized products toward α V β 6 was evaluated in competitive binding assays on isolated receptors, and α V β 6 /α V β 3 selectivity determined for a subgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity.