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

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 pKi 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. [Display omitted] ► Substituted styrene-amides are excellent CXCR7 binders. ► Computational model suggests important molecular descriptors. ► Key compounds induce recruitment of β-arrestin2 to CXCR7. ► Key compounds induce CXCR7 internalization.