Discovery and Optimization of -Acyl-6-sulfonamide-tetrahydroquinoline Derivatives as Novel Non-Steroidal Selective Glucocorticoid Receptor Modulators.

Selective glucocorticoid receptor modulators (SGRMs), which can dissociate the transactivation from the transrepression of the glucocorticoid receptor (GR), are regarded as very promising therapeutics for inflammatory and autoimmune diseases. We previously discovered a SGRM based on the passive antagonistic conformation of GR and bioassays. In this study, we further analyzed the dynamic changes of the passive antagonistic state upon the binding of and designed and synthesized 62 -acyl-6-sulfonamide-tetrahydroquinoline derivatives by structural optimization of . Therein, compound exhibits the best transrepression activity (IC = 0.009 ± 0.001 μM) comparable with dexamethasone (IC = 0.005 ± 0.001 μM) and no transactivation activity. can efficiently reduce the expression of inflammatory factors IL-6, IL-1β, TNF-α, and so on and makes a milder adverse effect and is highly specific to GR. Furthermore, is able to significantly relieve dermatitis on a mouse model via oral drug intervention.