Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists

Maikel Wijtmans, David Maussang, Francesco Sirci, Danny J. Scholten, Meritxell Canals, Azra Mujić-Delić, Milagros Chong, Kristell L S Chatalic, Hans Custers, Elwin Janssen, Chris De Graaf, Martine J. Smit, Iwan J P De Esch, Rob Leurs

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31 Citations (Scopus)

Abstract

The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the β-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pK i values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of β-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.

Original languageEnglish
Pages (from-to)184-192
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume51
DOIs
Publication statusPublished - May 2012
Externally publishedYes

Keywords

  • β-arrestin2
  • 3D fingerprint
  • Agonist
  • CXCR7
  • Internalization
  • Ligand

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