Nonsteroidal glucocorticoid agonists: Tetrahydronaphthalenes with alternative steroidal a-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity

被引：40

作者：

Biggadike, Keith ^{[1
]}

Boudjelal, Mohamed ^{[1
]}

Clackers, Margaret ^{[1
]}

Coe, Diane M. ^{[1
]}

Demaine, Derek A. ^{[1
]}

Hardy, George W. ^{[1
]}

Humphreys, Davina ^{[1
]}

Inglis, Graham G. A. ^{[1
]}

Johnston, Michael J. ^{[1
]}

Jones, Haydn T. ^{[1
]}

House, David ^{[1
]}

Loiseau, Richard ^{[1
]}

Needham, Deborah ^{[1
]}

Skone, Philip A. ^{[1
]}

Uings, Iain ^{[1
]}

Veitch, Gemma ^{[1
]}

Weingarten, Gordon G. ^{[1
]}

McLay, Iain M. ^{[1
]}

Macdonald, Simon J. F. ^{[1
]}

机构：

[1] Glaxo Smith Kline Res Ctr, Ri CEDD, Stevenage SG1 2NY, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 26期

关键词：

D O I：

10.1021/jm070778w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NF kappa B glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NF kappa B agonism with pIC(50) of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NF kappa B agonism with pIC(50) of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC(50) of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.

引用

页码：6519 / 6534

页数：16

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