Discovery of betamethasone 17α-carbamates as dissociated glucocorticoid receptor modulators in the rat

被引：10

作者：

Ali, Amjad ^{[1
]}

Balkovec, James M. ^{[1
]}

Greenlee, Mark ^{[1
]}

Hammond, Milton L. ^{[1
]}

Rouen, Greg ^{[1
]}

Taylor, Gayle ^{[1
]}

Einstein, Monica ^{[2
]}

Ge, Lan ^{[2
]}

Harris, Georgianna ^{[2
]}

Kelly, Terri M. ^{[2
]}

Mazur, Paul ^{[2
]}

Pandit, Shilpa ^{[2
]}

Santoro, Joseph ^{[2
]}

Sitlani, Ayesha ^{[2
]}

Wang, Chuanlin ^{[2
]}

Williamson, Joann ^{[3
]}

Forrest, Michael J. ^{[3
]}

Carballo-Jane, Ester ^{[3
]}

Luell, Silvi ^{[4
]}

Lowitz, Karen ^{[4
]}

Visco, Denise ^{[4
]}

机构：

[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Metab Disorders, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Pharmacol, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Lab Anim Resources, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 16期

关键词：

dissociated glucocorticoid receptor modulators; 17 alpha betamethasone carbamates; transactivation; transrepression; anti-inflammatory activity; impaired effects on glucose; insulin; triglycerides and body weights;

D O I：

10.1016/j.bmc.2008.07.037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

A series of betamethasone 17 alpha-carbamates were designed, synthesized, and evaluated for their ability to dissociate the two main functions of the glucocorticoid receptor, that is, transactivation and transrepression, in rat cell lines. A number of alkyl substituted betamethasone 17 alpha-carbamates were identified with excellent affinity for the glucocorticoid receptor (e.g., 7, GR IC(50) 5.1 nM) and indicated dissociated profiles in functional assays of transactivation (rat tyrosine aminotransferase, TAT, and rat glutamine synthetase, GS) and transrepression (human A549 cells, MMP-1 assay). Gratifyingly, the in-vivo profile of these compounds, for example, 7, also indicated potent anti-inflammatory activity with impaired effects on glucose, insulin, triglycerides, and body weight. Taken together, these results indicate that dissociated glucocorticoid receptor modulators can be identified in rodents. (C) 2008 Published by Elsevier Ltd.

引用

页码：7535 / 7542

页数：8

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