Discovery of the first potent and selective αvβ5 integrin inhibitor based on an amide-containing core

Integrins αvβ5 and αvβ3 are closely related, proangiogenic members of the wider RGD-binding integrin family. Due to their high sequence homology, the development of αvβ5-selective compounds has remained elusive to synthetic and medicinal chemists. Herein, we describe a survey of SAR around a series of amide-containing 3-aryl-succinamic acid-based RGD mimetics. This resulted in the discovery of α,α,α-trifluorotolyl 12 which exhibits 800 × selectivity for αvβ5 versus αvβ3 with a pyrrolidine amide linker that confers selectivity for αvβ5 by positioning a key aryl ring in the SDL of αvβ5 with good complementarity; binding in this mode is disfavoured in αvβ3 due to clashes with key residues in the β3-subunit. Compound 12 exhibits selective inhibition by a cell adhesion assay, high passive permeability and solubility which enables potential use of this inhibitor as an αvβ5-selective in vitro tool compound.