Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X7 antagonists

Derek W. Nelson; Robert J. Gregg; Michael E. Kort; Arturo Perez-Medrano; Eric A. Voight; Ying Wang; George Grayson; Marian T. Namovic; Diana L. Donnelly-Roberts; Wende Niforatos; Prisca Honore; Michael F. Jarvis; Connie R. Faltynek; William A. Carroll

doi:10.1021/jm051202e

Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X₇ antagonists

Derek W. Nelson^*, Robert J. Gregg, Michael E. Kort, Arturo Perez-Medrano, Eric A. Voight, Ying Wang, George Grayson, Marian T. Namovic, Diana L. Donnelly-Roberts, Wende Niforatos, Prisca Honore, Michael F. Jarvis, Connie R. Faltynek, William A. Carroll

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

223 Scopus citations

Abstract

1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X? receptor. Structure-activity relationship (SAR) studies were conducted around both the benzyl and phenyl moieties. In addition, the importance of the regiochemical substitution on the tetrazole was examined. Compounds were evaluated for activity to inhibit calcium flux in both human and rat recombinant P2X₇ cell lines using fluorometric imaging plate reader technology. Analogues were also assayed for their ability to inhibit IL-1β release and to inhibit P2X₇-mediated pore formation in human THP-1 cells. Compound 15d was advanced to efficacy studies in a model of neuropathic pain where significant reversal of mechanical allodynia was observed at doses that did not affect motor coordination.

Original language	English (US)
Pages (from-to)	3659-3666
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	49
Issue number	12
DOIs	https://doi.org/10.1021/jm051202e
State	Published - Jun 15 2006

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/jm051202e

Cite this

Nelson, D. W., Gregg, R. J., Kort, M. E., Perez-Medrano, A., Voight, E. A., Wang, Y., Grayson, G., Namovic, M. T., Donnelly-Roberts, D. L., Niforatos, W., Honore, P., Jarvis, M. F., Faltynek, C. R., & Carroll, W. A. (2006). Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X₇ antagonists. Journal of Medicinal Chemistry, 49(12), 3659-3666. https://doi.org/10.1021/jm051202e

@article{4f1e6942cf974edebd9c10f563f5979c,

title = "Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X7 antagonists",

abstract = "1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X? receptor. Structure-activity relationship (SAR) studies were conducted around both the benzyl and phenyl moieties. In addition, the importance of the regiochemical substitution on the tetrazole was examined. Compounds were evaluated for activity to inhibit calcium flux in both human and rat recombinant P2X7 cell lines using fluorometric imaging plate reader technology. Analogues were also assayed for their ability to inhibit IL-1β release and to inhibit P2X7-mediated pore formation in human THP-1 cells. Compound 15d was advanced to efficacy studies in a model of neuropathic pain where significant reversal of mechanical allodynia was observed at doses that did not affect motor coordination.",

author = "Nelson, {Derek W.} and Gregg, {Robert J.} and Kort, {Michael E.} and Arturo Perez-Medrano and Voight, {Eric A.} and Ying Wang and George Grayson and Namovic, {Marian T.} and Donnelly-Roberts, {Diana L.} and Wende Niforatos and Prisca Honore and Jarvis, {Michael F.} and Faltynek, {Connie R.} and Carroll, {William A.}",

year = "2006",

month = jun,

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language = "English (US)",

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publisher = "American Chemical Society",

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Nelson, DW, Gregg, RJ, Kort, ME, Perez-Medrano, A, Voight, EA, Wang, Y, Grayson, G, Namovic, MT, Donnelly-Roberts, DL, Niforatos, W, Honore, P, Jarvis, MF, Faltynek, CR & Carroll, WA 2006, 'Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X₇ antagonists', Journal of Medicinal Chemistry, vol. 49, no. 12, pp. 3659-3666. https://doi.org/10.1021/jm051202e

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AU - Nelson, Derek W.

AU - Gregg, Robert J.

AU - Kort, Michael E.

AU - Perez-Medrano, Arturo

AU - Voight, Eric A.

AU - Wang, Ying

AU - Grayson, George

AU - Namovic, Marian T.

AU - Donnelly-Roberts, Diana L.

AU - Niforatos, Wende

AU - Honore, Prisca

AU - Jarvis, Michael F.

AU - Faltynek, Connie R.

AU - Carroll, William A.

PY - 2006/6/15

Y1 - 2006/6/15

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AB - 1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X? receptor. Structure-activity relationship (SAR) studies were conducted around both the benzyl and phenyl moieties. In addition, the importance of the regiochemical substitution on the tetrazole was examined. Compounds were evaluated for activity to inhibit calcium flux in both human and rat recombinant P2X7 cell lines using fluorometric imaging plate reader technology. Analogues were also assayed for their ability to inhibit IL-1β release and to inhibit P2X7-mediated pore formation in human THP-1 cells. Compound 15d was advanced to efficacy studies in a model of neuropathic pain where significant reversal of mechanical allodynia was observed at doses that did not affect motor coordination.

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