Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: survival of the fittest regulator of the immune system?
The search for novel glucocorticoid receptor (GR) modulators with similar anti-inflammatory properties as conventional steroids, but with a reduction in the number or severity of the side effects has been a long-standing goal, and still remains a challenge today. The quest for these so-called 'dissociated GR ligands' is mainly based on the hypothesis that the occurrence of undesirable side effects is mostly associated with GR-mediated transactivation, whereas transrepression of many pro-inflammatory genes (e.g. cytokines and enzymes involved in inflammatory processes) is more involved in GR-mediated anti-inflammatory effects. As glucocorticoids (GCs) can also enhance the transcription of anti-inflammatory genes, the GR-mediated activation-repression dissociation hypothesis has to be nuanced. However, an enhanced selectivity of GR-affected genes, while upholding the desired anti-inflammatory potential, is still believed to contribute to a more beneficial therapeutic profile with fewer side effects. The initial pharmacological focus on steroidal scaffolds as a basis to dissociate the functionalities of GR has, due to a lack of success, recently been shifted to a focus on non-steroidal ligands. The current work reviews recent advances on the characterization of a generation of novel non-steroidal GR ligands.
De Bosscher
Karolien
K
Laboratory of Eukaryotic Gene Expression & Signal Transduction, Department of Physiology, Ghent University, K.L. Ledeganckstraat 35, Gent, Belgium. Karolien.DeBosscher@UGent.be
Beck
Ilse M
IM
Haegeman
Guy
G
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology; D005938:Glucocorticoids / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000378:metabolism; D007155:Immunologic Factors / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology*; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology
C476829:10-methoxy-5-(2-propenyl)-2,5-dihydro-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinoline; C525875:5-((2-fluoro-3-methylphenyl)methylene)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinolin-9-ol; D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D001597:Benzylidene Compounds; D005938:Glucocorticoids; D007155:Immunologic Factors; D018836:Inflammation Mediators; D011720:Pyrazoles; D011804:Quinolines; D011965:Receptors, Glucocorticoid; C031280:pyrazole