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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.
Original language | English |
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Article number | 112719 |
Number of pages | 76 |
Journal | European Journal of Medicinal Chemistry |
Volume | 208 |
Early online date | 25 Aug 2020 |
DOIs | |
Publication status | Published - 15 Dec 2020 |
Keywords
- avb5
- Homology
- Integrins
- Selective
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Supplementary data for "Discovery of the first potent and selective αvβ5 integrin inhibitor based on an amide-containing core"
Murphy, J. (Creator), Lippa, R. (Creator), Barrett, J. W. (Creator), Pal, S. (Creator), Rowedder, J. E. (Creator) & Barrett, T. N. (Creator), University of Strathclyde, 18 Feb 2020
DOI: 10.15129/a3237b0f-5b61-4da0-b78b-526726c136d1
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