Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands

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

doi:10.1021/jm301240t

Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands

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

Drug Discovery Biology

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Abstract

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-activity relationship and structure-function 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.

Original language	English
Pages (from-to)	10572-10583
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	23
DOIs	https://doi.org/10.1021/jm301240t
Publication status	Published - 13 Dec 2012

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Wijtmans, M., Scholten, D. J., Roumen, L., Canals, M., Custers, H., Glas, M., Vreeker, M. C. A., De Kanter, F. J. J., de Graaf, C., Smit, M. J., de Esch, I. J. P., & Leurs, R. (2012). Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands. Journal of Medicinal Chemistry, 55(23), 10572-10583. https://doi.org/10.1021/jm301240t

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title = "Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands",

abstract = "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-activity relationship and structure-function 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.",

author = "Maikel Wijtmans and Scholten, {Danny J.} and Luc Roumen and Meritxell Canals and Hans Custers and Marjolein Glas and Vreeker, {Marlies C. A.} and {De Kanter}, {Frans J. J.} and {de Graaf}, Chris and Smit, {Martine J.} and {de Esch}, {Iwan J. P.} and Rob Leurs",

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Wijtmans, M, Scholten, DJ, Roumen, L, Canals, M, Custers, H, Glas, M, Vreeker, MCA, De Kanter, FJJ, de Graaf, C, Smit, MJ, de Esch, IJP & Leurs, R 2012, 'Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands', Journal of Medicinal Chemistry, vol. 55, no. 23, pp. 10572-10583. https://doi.org/10.1021/jm301240t

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T1 - Chemical subtleties in small-molecule modulation of peptide receptor function

T2 - the case of CXCR3 biaryl-type ligands

AU - Wijtmans, Maikel

AU - Scholten, Danny J.

AU - Roumen, Luc

AU - Canals, Meritxell

AU - Custers, Hans

AU - Glas, Marjolein

AU - Vreeker, Marlies C. A.

AU - De Kanter, Frans J. J.

AU - de Graaf, Chris

AU - Smit, Martine J.

AU - de Esch, Iwan J. P.

AU - Leurs, Rob

PY - 2012/12/13

Y1 - 2012/12/13

N2 - 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-activity relationship and structure-function 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.

AB - 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-activity relationship and structure-function 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.

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JO - Journal of Medicinal Chemistry

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ER -

Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands

Abstract

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