A Novel Antiinflammatory Maintains Glucocorticoid Efficacy with Reduced Side Effects

Abstract

Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor gamma coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.

A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis

“…This insight initiated a new wave of pharmacological research directed toward the development of so-called dissociated ligands, favoring only GR-mediated transrepression of NF-B-or AP-1-driven gene expression (35)(36)(37)(38). Surprisingly, not all steroidal ligands that had dissociated properties in vitro also displayed these characteristics in vivo, especially with regard to the side-effect profile (35).…”

Cross-talk between nuclear receptors and nuclear factor κB

“…Second, AL-438, derived by modifying a synthetic progestin scaffold, was found to be completely competent for transcriptional repression of NF-kB-driven genes, but only a partial agonist for GR-mediate transcriptional activation, and thus capable of separating at least some GR activities in a genespecific manner. The mechanism of action of AL-438 involves differential coactivator recruitments of GRIP1/ TIF2 versus PGC-1; the latter seems preferentially used in steroid-mediated glucose upregulation (Coghlan et al, 2003). Third, a series of related arylpyrazole compounds can elicit different expression patterns on 17 endogenous GR target genes in different cell types (i.e., lung, preadipocyte and preosteoblast), demonstrating that subtle differences in ligand structure can have profound effects on transcriptional regulatory activities of NRs (Wang et al, 2006).…”

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

“…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).…”

“…There are a number of GC-inducible genes with anti-inflammatory effects that have been discovered, indicating that transactivation also contributes to the anti-inflammatory effects (16)(17)(18)(19)(20)(21)(22)(23)(24). As a result, novel compounds that lack capacity for steroid-inducible genes may in fact show lessened anti-inflammatory effects (9)(10)(11). Therefore, the goal has focused primarily on developing novel GR ligands that induce a just a subset of GR activities (25)(26)(27).…”