Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors

被引：121

作者：

Cote, Bernard ^{[1
]}

Boulet, Louise ^{[1
]}

Brideau, Christine ^{[1
]}

Claveau, David ^{[1
]}

Ethier, Diane ^{[1
]}

Frenette, Richard ^{[1
]}

Gagnon, Marc ^{[1
]}

Giroux, Andre ^{[1
]}

Guay, Jocelyne ^{[1
]}

Guiral, Sebastien ^{[1
]}

Mancini, Joseph ^{[1
]}

Martins, Evelyn ^{[1
]}

Masse, Frederic ^{[1
]}

Methot, Nathalie ^{[1
]}

Riendeau, Denis ^{[1
]}

Rubin, Joel ^{[1
]}

Xu, Daigen ^{[1
]}

Yu, Hongping ^{[1
]}

Ducharme, Yves ^{[1
]}

Friesen, Richard W. ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Kirkland, PQ H9H 3L1, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 24期

关键词：

mPGES-1; PGE(2); inflammation; prostanoid;

D O I：

10.1016/j.bmcl.2007.10.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid I with an A549 whole cell IC50 of 0.42 mu M (50% FBS) and a human whole blood IC50 of 1.3 mu M. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100 mg/kg. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：6816 / 6820

页数：5

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