The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation

被引：26

作者：

Edman, Karl ^{[1
]}

Ahlgren, Ragnhild ^{[2
]}

Bengtsson, Malena ^{[2
]}

Bladh, Hakan ^{[2
]}

Backstrom, Stefan ^{[1
]}

Dahmen, Jan ^{[2
]}

Henriksson, Krister ^{[2
]}

Hillertz, Per ^{[1
]}

Hulikal, Vijakumar ^{[2
]}

Jerre, Anders ^{[2
]}

Kinchin, Liz ^{[2
]}

Kase, Charlotte ^{[2
]}

Lepisto, Matti ^{[3
]}

Mile, Irene ^{[2
]}

Nilsson, Stinabritt ^{[2
]}

Smailagic, Amir ^{[3
]}

Taylor, John ^{[3
]}

Tjornebo, Ann ^{[2
]}

Wissler, Lisa ^{[1
]}

Hansson, Thomas ^{[3
]}

机构：

[1] AstraZeneca R&D, Discovery Sci, Innovat Med, SE-43183 Molndal, Sweden

[2] AstraZeneca R&D, S-22187 Lund, Sweden

[3] AstraZeneca R&D, Innovat Med, Resp Inflammat & Autoimmun, SE-43183 Molndal, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 11期

关键词：

Glucocorticoid receptor; Non-steroidal selective glucocorticoid; receptor modulators; Inhalation; Indazoles; LIGAND-BINDING DOMAIN; FLUTICASONE FUROATE; CRYSTAL-STRUCTURE; AGONIST;

D O I：

10.1016/j.bmcl.2014.03.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：2571 / 2577

页数：7

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