title: Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists.
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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
authors.forename: David
authors.initials: D
authors.lastname: Maussang
authors.forename: Francesco
authors.initials: F
authors.lastname: Sirci
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Scholten
authors.forename: Meritxell
authors.initials: M
authors.lastname: Canals
authors.forename: Azra
authors.initials: A
authors.lastname: Mujić-Delić
authors.forename: Milagros
authors.initials: M
authors.lastname: Chong
authors.forename: Kristell L S
authors.initials: KL
authors.lastname: Chatalic
authors.forename: Hans
authors.initials: H
authors.lastname: Custers
authors.forename: Elwin
authors.initials: E
authors.lastname: Janssen
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000577:Amides / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D054387:Receptors, CXCR / Q000819:agonists*; D020058:Styrene / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C501896:ACKR3 protein, human; D000577:Amides; D054387:Receptors, CXCR; D020058:Styrene