3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity

被引：23

作者：

Fisher, Matthew J. ^{[1
]}

Backer, Ryan T. ^{[1
]}

Barth, Vanessa N. ^{[1
]}

Garbison, Kim E. ^{[1
]}

Gruber, Joseph M. ^{[1
]}

Heinz, Beverly A. ^{[1
]}

Iyengar, Smriti ^{[1
]}

Hollinshead, Sean P. ^{[1
]}

Kingston, Anne ^{[1
]}

Kuklish, Steven L. ^{[1
]}

Li, Linglin ^{[1
]}

Nisenbaum, Eric S. ^{[1
]}

Peters, Steven C. ^{[1
]}

Phebus, Lee ^{[1
]}

Simmons, Rosa Maria A. ^{[1
]}

van der Aar, Ellen ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 07期

关键词：

mGluR1; Receptor occupancy; Formalin model; METABOTROPIC GLUTAMATE RECEPTORS; ALLOSTERIC MODULATORS; ANTISENSE KNOCKDOWN; DOPAMINE D2; OCCUPANCY; BRAIN; PAIN; EFFICACY; A-841720; MODELS;

D O I：

10.1016/j.bmcl.2012.02.003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2514 / 2517

页数：4

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