JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits improved transrepression/transactivation dissociation

A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation

“…Dex is a strong classical synthetic steroid 25 times more effective than hydrocortisone 33 . Compounds were selected based on frequent clinical use (Prednisolone is six times less effective than Dex 33 ), based on previously described TA versus TR-dissociating activities (Fosdagrocorat 21 , 34 , Mapracorat 22 and LGD5552 23 , 35 , representing negative selectors 9 ), or based on their previously described high affinity and strong GR agonist profile (Cortivazol 24 , 25 and AZD2906 26 , 27 ).…”

“…First, dissociating GR TA from TR to separate the GC side effects from the anti-inflammatory effects is an overly simplified model because particular side effects are still found in GR dim mice and thus are considered as monomer-dependent 55 , 56 . Second, most of the research focusing on decreased GR TA may have been complicated by a simultaneous loss of TR resulting in generally less performant GCs (as is the case of Fosdagrocorat) 21 , 34 . Third, the contribution of the induction of GR dimers and thus TA of GRE-containing genes coding for anti-inflammatory proteins, such as TSC22D3 and DUSP1 , has been widely underestimated in the anti-inflammatory success of GCs 57 – 61 .…”

Glucocorticoid receptor modulators

“…far there have been no clinical breakthroughs of this kind of molecules(13), but developments are still on-going(14). However, the notion of gaining specificity of cortisol effects by dissociating GR signallingpathways still bears substantial promise -if only because ligands for the related estrogen receptor (ER) show proof of principle.…”

The Future of Steroid Therapy in Inflammatory Disease

“…Of these Compound A (CpdA) was the earliest to be identified and was first isolated from the Namibian shrub (Salsola tuberculatiformis). This non-steroidal compound when investigated was found to bind atypically to the GR in ligand binding essays but with high affinity, and was thought it may be using different coupling points in the Ligand binding domain of the GR or by inducing a unique conformation of the GR which is not yet understood [20][21][22][23][24].…”

“…As such this is a very interesting compound which can be used as a platform to study future SERMs and is being suggested for phase 1 clinical trials in an MS model [21]. Table 1: List of known SGRMs/SERMS and their profile of action [19][20][21][22][23].…”