Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series

Barker, Mike D.; Clackers, Margaret; Copley, Royston C. B.; Demaine, Derek A.; Humphreys, Davina; Inglis, Graham G. A.; Johnston, Michael J.; Jones, Haydn T.; Haase, Michael V.; House, David; Loiseau, Richard; Nisbet, Lesley; Pacquet, François; Skone, Philip A.; Shanahan, Stephen E.; Tape, Dan; Vinader, V.; Washington, Melanie; Uings, Iain; Upton, Richard J.; McLay, Iain M.; Macdonald, Simon J. F.

doi:10.1021/jm060302x

Cited by 76 publications

(48 citation statements)

References 22 publications

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“…Compounds described to date have been both steroidal (20) and nonsteroidal (19,21,22) and have various activities that suggest a separation from steroidal side effects (5). Strong in vivo separation between efficacy and side effects is generally lacking in the published literature with a few exceptions: Schacke et al (23) published separation in vivo for topical application, and Coghlan et al (5,6,21,22,24) published separation between efficacy and side effects in vivo after oral administration. Others have published various nonsteroidal compounds with interesting activity in vitro (25)(26)(27) and some demonstrating antiinflammatory activity in vivo, but no side-effect data (27).…”

Section: Discussionmentioning

confidence: 99%

Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

Miner

Ardecky²,

Benbatoul³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.selective glucocorticoid receptor modulator (SGRM) ͉ nonsteroid ͉ dissociated ͉ repression

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Section: Discussionmentioning

confidence: 99%

Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

Miner

Ardecky²,

Benbatoul³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Along with RU24858, numerous steroidal and nonsteroidal ligands of GR show various degrees of dissociated function based on standard reporter assays (Elmore et al, 2001(Elmore et al, , 2004Shah and Scanlan, 2004;De Bosscher et al, 2005;Barker et al, 2006;Wang et al, 2006a). Although a number of these compounds show anti-inflammatory activity, detailed descriptions with respect to inducible genes or side effects are not reported.…”

Section: Gr Ligands and Functionmentioning

confidence: 99%

Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor?

Newton

Holden²

2007

Mol Pharmacol

280

263

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Glucocorticoids (corticosteroids) are highly effective in combating inflammation in the context of a variety of diseases. However, clinical utility can be compromised by the development of side effects, many of which are attributed to the ability of the glucocorticoid receptor (GR) to induce the transcription of, or transactivate, certain genes. By contrast, the anti-inflammatory effects of glucocorticoids are due largely to their ability to reduce the expression of pro-inflammatory genes. This effect has been predominantly attributed to the repression of key inflammatory transcription factors, including AP-1 and NF-B, and is termed transrepression. The ability to functionally separate these transcriptional functions of GR has prompted a search for dissociated GR ligands that can differentially induce transrepression but not transactivation. In this review, we present evidence that post-transcriptional mechanisms of action are highly important to the anti-inflammatory actions of glucocorticoids. Furthermore, we present the case that mechanistically distinct forms of glucocorticoid-inducible gene expression are critical to the development of anti-inflammatory effects by repressing inflammatory signaling pathways and inflammatory gene expression at multiple levels. Considerable care is therefore required to avoid loss of anti-inflammatory effectiveness in the development of novel transactivation-defective ligands of GR.

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“…The hypothesis that the active and repressive functions of GR are responsible for negative side effects and anti-inflammatory effects, respectively, has led to the discovery of a number of interesting compounds (2,3,(8)(9)(10)(11)(12)(13)(14). However, accumulating evidence suggests that the transcriptional repression by GR alone does not fully account for the repression of inflammatory genes (15).…”

mentioning

confidence: 99%

Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

Cheng

Zhu

et al. 2011

The Journal of Immunology

100

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Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, they cause debilitating side effects, which limit the use of these compounds. In the past decade, many researchers have attempted to find so-called dissociated GCs that have separate distinct transactivation and transrepression activities. Anti-inflammation of GCs is a result of glucocorticoid receptor (GR)-mediated transactivation and transrepression in some tissues, similar to their side effects; therefore, the goal to discover a compound that has anti-inflammatory properties, but lacks the negative side effects seen with GCs, has yet to be achieved. In the present study, we introduce a plant-derived compound, ginsenoside Rg1, which possesses GC and estrogen-like activities. In this study, we show that Rg1 downmodulates LPS-induced proinflammatory cytokine release and inhibits NF-κB nuclear translocation and DNA binding activity. The negative effects on NF-κB activation are due to a decrease in IκB phosphorylation and protein stabilization. Furthermore, the inhibitory effect of Rg1 on NF-κB is GR-dependent, as small interfering RNA knockdown of GR abrogated this function. Rg1 also displayed profound inhibitory effects on LPS-induced MAPK activation. Importantly, Rg1 did not impair proliferation or differentiation of mouse osteoblasts. Finally, we show that Rg1 can effectively inhibit acute and chronic inflammation in vivo, but it does not cause hyperglycemia or osteoporosis as seen with dexamethasone. These results suggest that ginsenoside Rg1 may serve as a novel anti-inflammatory agent and may exhibit a potential profile for therapeutic intervention in inflammatory diseases.

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Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series

Cited by 76 publications

References 22 publications

Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor?

Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

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