Chemical Subtleties in Small-Molecule Modulation of Peptide Receptor Function: The Case of CXCR3 Biaryl-Type Ligands

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• 作者：Maikel Wijtmans ; Danny J. Scholten ; Luc Roumen ; Meritxell Canals ; Hans Custers ; Marjolein Glas ; Marlies C. A. Vreeker ; Frans J. J. de Kanter ; Chris de Graaf ; Martine J. Smit ; Iwan J. P. de Esch ; Rob Leurs
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10572-10583
• 全文大小：591K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

The G protein-coupled chemokine receptor CXCR3 plays a role in numerous inflammatory events. The endogenous ligands for the chemokine receptors are peptides, but in this study we disclose small-molecule ligands that are able to activate CXCR3. A class of biaryl-type compounds that is assembled by convenient synthetic routes is described as a new class of CXCR3 agonists. Intriguingly, structure鈥揳ctivity relationship and structure鈥揻unction relationship studies reveal that subtle chemical modifications on the outer aryl ring (e.g., either the size or position of a halogen atom) result in a full spectrum of agonist efficacies on CXCR3. Quantum mechanics calculations and nuclear Overhauser effect spectroscopy NMR studies suggest that the biaryl dihedral angle and the electronic nature of ortho-substituents play an important role in determining agonist efficacies. Compounds 38 (VUF11222) and 39 (VUF11418) are the first reported nonpeptidomimetic agonists on CXCR3, rendering them highly useful chemical tools for detailed assessment of CXCR3 activation as well as for studying downstream CXCR3 signaling.