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

Lippa, Rhys A. and Barrett, John and Pal, Sandeep and Rowedder, James E. and Murphy, John A. and Barrett, Tim N. (2020) Discovery of the first potent and selective αvβ5 integrin inhibitor based on an amide-containing core. European Journal of Medicinal Chemistry, 208. 112719. ISSN 0223-5234 (https://doi.org/10.1016/j.ejmech.2020.112719)

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Abstract

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.

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