trans-Activation and Repression Properties of the Novel Nonsteroid Glucocorticoid Receptor Ligand 2,5-Dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and Its Four Stereoisomers

Abstract

Glucocorticoids are potent anti-inflammatory and immunosuppressant agents. However, they also produce serious side effects that limit their usage. It has been proposed that antiinflammatory properties of glucocorticoids are caused mostly by repression of activator protein 1-and nuclear factor ␤-stimulated synthesis of inflammatory mediators, whereas most of their adverse effects are associated with trans-activation of genes involved with metabolic processes. Our laboratories have sought to discover novel glucocorticoid receptor (GR) ligands that have high repression but low trans-activation activities. We describe here cellular properties of 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and its four enantiomers. Similar to dexamethasone, A276575 exhibited high affinity for GR and potently repressed interleukin (IL) 1␤-stimulated IL-6 production in human skin fibroblasts, prostaglandin (PG) E 2 production in A549 human lung epithelial cells, and concanavalin A-induced monocyte proliferation. In con-

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

“…The development of selective GR agonists (28) that target the transrepressive effects of GCs over the tranasctivating actions looks promising (29,30) but a clinical drug has not yet been delivered. Numerous selective 11β-HSD1 inhibitors have been developed and many tested in phase II studies (12,13); their evaluation in patients with Cushing syndrome will be of great interest.…”

Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

“…"transactivation", which is thought to be responsible for most of the adverse reactions [3], and "transrepression", which is considered to mediate numerous desirable anti-inflammatory and immunomodulating effects [45]. Hence, "dissociating glucocorticoids" or so called "selective glucocorticoid receptor agonists (SEGRA's)" are in the development pipeline.…”

“…However, in the last years an increasing number of SEGRA's has been described. A very interesting substance is for example A276575 and its four enantiomeres [45], all ligands that bind with the same affinity to the cGCR as dexamethasone does. These novel GCR ligands repress IL-1α-induced IL-6 production.…”

The Clinical Role of Glucocorticoids in the Management of Rheumatoid Arthritis

“…Despite showing initial promise in dissociation of GC mediated gene activation and repression, the in-vivo effects were more disappointing and the drug did not make it into clinical trials (Belvisi et al, 2001). Other drugs such as A276575 have again shown promise but fared little better (Lin et al, 2002). The only SEGRA in clinical trials at the moment is ZK 245186 which is in Phase III trials for topical use post cateract surgery after initial results from animal models showed promise (Proksch et al, 2011).…”