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

Rhys A. Lippa, John Barrett, Sandeep Pal, James E. Rowedder, John A. Murphy, Tim N. Barrett

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Article number112719
Number of pages76
JournalEuropean Journal of Medicinal Chemistry
Early online date25 Aug 2020
Publication statusPublished - 15 Dec 2020


  • avb5
  • Homology
  • Integrins
  • Selective

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