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

M. Wijtmans, D.J. Scholten, L. Roumen, M. Canals, H. Custers, M. Glas, M. Vreeker, C. de Graaf, M.J. Smit, I.J.P. de Esch, R. Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

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. © 2012 American Chemical Society.
Original languageEnglish
Pages (from-to)10572-10583
JournalJournal of Medicinal Chemistry
Volume55
DOIs
Publication statusPublished - 2012

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Peptide Receptors
Chemokine Receptors
Ligands
Halogens
Structure-Activity Relationship
G-Protein-Coupled Receptors
Mechanics
Magnetic Resonance Spectroscopy
Peptides

Cite this

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title = "Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 bisaryl-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. {\circledC} 2012 American Chemical Society.",
author = "M. Wijtmans and D.J. Scholten and L. Roumen and M. Canals and H. Custers and M. Glas and M. Vreeker and {de Graaf}, C. and M.J. Smit and {de Esch}, I.J.P. and R. Leurs",
year = "2012",
doi = "10.1021/jm301240t",
language = "English",
volume = "55",
pages = "10572--10583",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",

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Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 bisaryl-type ligands. / Wijtmans, M.; Scholten, D.J.; Roumen, L.; Canals, M.; Custers, H.; Glas, M.; Vreeker, M.; de Graaf, C.; Smit, M.J.; de Esch, I.J.P.; Leurs, R.

In: Journal of Medicinal Chemistry, Vol. 55, 2012, p. 10572-10583.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 bisaryl-type ligands

AU - Wijtmans, M.

AU - Scholten, D.J.

AU - Roumen, L.

AU - Canals, M.

AU - Custers, H.

AU - Glas, M.

AU - Vreeker, M.

AU - de Graaf, C.

AU - Smit, M.J.

AU - de Esch, I.J.P.

AU - Leurs, R.

PY - 2012

Y1 - 2012

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. © 2012 American Chemical Society.

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. © 2012 American Chemical Society.

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JO - Journal of Medicinal Chemistry

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