Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators

被引：18

作者：

Hemmerling, Martin ^{[1
]}

Edman, Karl ^{[2
]}

Lepisto, Matti ^{[1
]}

Eriksson, Anders ^{[1
]}

Ivanova, Svetlana ^{[3
]}

Dahmen, Jan ^{[3
]}

Rehwinkel, Hartmut ^{[4
]}

Berger, Markus ^{[4
]}

Hendrickx, Ramon ^{[1
]}

Dearman, Matthew ^{[1
]}

Jensen, Tina Jellesmark ^{[1
]}

Wissler, Lisa ^{[2
]}

Hansson, Thomas ^{[1
]}

机构：

[1] AstraZeneca, Resp Inflammat & Autoimmun Innovat Med & Early De, Pepparedsleden 1, S-43183 Molndal, Sweden

[2] AstraZeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Pepparedsleden 1, S-43183 Molndal, Sweden

[3] AstraZeneca R&D, Scheelevagen 1, S-22187 Lund, Sweden

[4] Bayer Pharma AG, Med Chem Berlin, Candidate Generat & External Innovat, Drug Discovery, D-13353 Berlin, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 23期

关键词：

Non-steroidal glucocorticoid; Glucocorticoid receptor modulators; Indazoles; Anti-inflammatory activity; INHALED CORTICOSTEROIDS; AGONISTS;

D O I：

10.1016/j.bmcl.2016.10.052

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A structure-based design approach led to the identification of a novel class of indazole ether based, nonsteroidal glucocorticoid receptor (GR) modulators. Several examples were identified that displayed cell potency in the picomolar range, inhibiting LPS-induced TNF-alpha release by primary peripheral blood mononuclear cells (PBMCs). Additionally, an improved steroid hormone receptor binding selectivity profile, compared to classical steroidal GR agonists, was demonstrated. The indazole ether core tolerated a broad range of substituents allowing for modulation of the physiochemical parameters. A small subset of indazole ethers, with pharmacokinetic properties suitable for oral administration, was investigated in a rat antigen-induced joint inflammation model and demonstrated excellent anti-inflammatory efficacy. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：5741 / 5748

页数：8

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