Pharmacophoric Modifications Lead to Superpotent αvβ3 Integrin Ligands with Suppressed α5β1 Activity

The selective targeting of the alpha v beta 3 integrin subtype without affecting the structurally closely related receptor alpha 5 beta 1 is crucial for understanding the details of their biological and pathological functions and thus of great relevance for diagnostic and therapeutic approaches in cancer treatment. Here, we present the synthesis of highly active RGD peptidomimetics for the alpha v beta 3 integrin with remarkable selectivity against alpha 5 beta 1. Incorporation of a methoxypyridine building block into a ligand scaffold and variation of different functional moieties led to alpha v beta 3-antagonistic activities in the low nanomolar or even subnanomolar range. Furthermore, docking studies were performed to give insights into the binding modes of the novel compounds. The presented library comprises powerful ligands for specific addressing and blocking of the alpha v beta 3 integrin subtype, thereby representing privileged tools for integrin-based personalized medicine.