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

被引：206

作者：

Nelson, Derek W. ^{[1
]}

Gregg, Robert J. ^{[1
]}

Kort, Michael E. ^{[1
]}

Perez-Medrano, Arturo ^{[1
]}

Voight, Eric A. ^{[1
]}

Wang, Ying ^{[1
]}

Grayson, George ^{[1
]}

Namovic, Marian T. ^{[1
]}

Donnelly-Roberts, Diana L. ^{[1
]}

Niforatos, Wende ^{[1
]}

Honore, Prisca ^{[1
]}

Jarvis, Michael F. ^{[1
]}

Faltynek, Connie R. ^{[1
]}

Carroll, William A. ^{[1
]}

机构：

[1] Abbott Labs, Neurosci Res, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 12期

关键词：

D O I：

10.1021/jm051202e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X(7) 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-1 beta release and to inhibit P2X(7)-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.

引用

页码：3659 / 3666

页数：8

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