Rational Design of Highly Active and Selective Ligands for the α5β1 Integrin Receptor

Abstract The inhibition of integrin function is a major challenge in medicinal chemistry. Potent ligands are currently in different stages of clinical trials for the antiangiogenic therapy of cancer and age‐related macula degeneration (AMD). The subtype α5β1 has recently been drawn into the focus of research because of its genuine role in angiogenesis. In our previous work we could demonstrate that the lack of structural information about the receptor could be overcome by a homology model based on the X‐ray structure of the αvβ3 integrin subtype and the sequence similarities between both receptors. In this work, we describe the rational design and synthesis of high affinity α5β1 binders, and the optimisation of selectivity against αvβ3 by means of extensive SAR studies and docking experiments. A first series of compounds based on the tyrosine scaffold resulted in affinities in the low and even subnanomolar range and selectivities of 400‐fold against αvβ3. The insights about the structure–activity relationship gained from tyrosine‐based ligands could be successfully transferred to ligands that bear an aza‐glycine scaffold to yield α5β1 ligands with affinities of ∼1 nm and selectivities that exceed 10 4 ‐fold. The ligands have already been successfully employed as selective α5β1 ligands in biological research and might serve as lead structures for antiangiogenic cancer therapy.