Dissociated nonsteroidal glucocorticoid receptor modulators; Discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series

被引：79

作者：

Barker, Mike ^{[1
]}

Clackers, Margaret ^{[1
]}

Copley, Royston ^{[1
]}

Demaine, Derek A. ^{[1
]}

Humphreys, Davina ^{[1
]}

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

Johnston, Michael J. ^{[1
]}

Jones, Haydn T. ^{[1
]}

Haase, Michael V. ^{[1
]}

House, David ^{[1
]}

Loiseau, Richard ^{[1
]}

Nisbet, Lesley ^{[1
]}

Pacquet, Francois ^{[1
]}

Skone, Philip A. ^{[1
]}

Shanahan, Stephen E. ^{[1
]}

Tape, Dan ^{[1
]}

Vinader, Victoria M. ^{[1
]}

Washington, Melanie ^{[1
]}

Uings, Iain ^{[1
]}

Upton, Richard ^{[1
]}

Mclay, Iain M. ^{[1
]}

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

机构：

[1] RI CEDD, GlaxoSmithKline Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 14期

关键词：

D O I：

10.1021/jm060302x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay ( representing transrepression effects) over an MMTV GR agonist assay ( representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.

引用

页码：4216 / 4231

页数：16

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