Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor

被引：10

作者：

Burch, Jason D. ^{[1
]}

Farand, Julie ^{[1
]}

Colucci, John ^{[1
]}

Sturino, Claudio ^{[1
]}

Ducharme, Yves ^{[1
]}

Friesen, Richard W. ^{[1
]}

Levesque, Jean-Francois ^{[2
]}

Gagne, Sebastien ^{[2
]}

Wrona, Mark ^{[2
]}

Therien, Alex G. ^{[3
]}

Mathieu, Marie-Claude ^{[3
]}

Denis, Danielle ^{[3
]}

Vigneault, Erika ^{[3
]}

Xu, Daigen ^{[4
]}

Clark, Patsy ^{[4
]}

Rowland, Steve ^{[4
]}

Han, Yongxin ^{[1
]}

机构：

[1] Merck Frosst Canada Ltd, Dept Med Chem, Merck Frosst Ctr Therapeut Res, Kirkland, PQ H9H 3L1, Canada

[2] Merck Frosst Canada Ltd, Dept DMPK, Merck Frosst Ctr Therapeut Res, Kirkland, PQ H9H 3L1, Canada

[3] Merck Frosst Canada Ltd, Dept In Vitro Sci, Merck Frosst Ctr Therapeut Res, Kirkland, PQ H9H 3L1, Canada

[4] Merck Frosst Canada Ltd, Dept In Vivo Sci, Merck Frosst Ctr Therapeut Res, Kirkland, PQ H9H 3L1, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 03期

关键词：

Naphthalene/quinoline amides and sulfonylureas; EP4 receptor antagonist; Inflammatory pain; PROSTANOID RECEPTORS; COX-2; INHIBITORS; CANCER CELLS; PROMOTES; EXPRESSION; GROWTH; PAIN; INFLAMMATION; METASTASIS; REDUCTION;

D O I：

10.1016/j.bmcl.2010.12.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two new series of EP4 antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP4 receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：1041 / 1046

页数：6

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