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 HP-19 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 HP-19 and designed
and synthesized 62 N-acyl-6-sulfonamide-tetrahydroquinoline
derivatives by structural optimization of HP-19. Therein,
compound B53 exhibits the best transrepression activity
(IC50NF‑κB = 0.009 ± 0.001
μM) comparable with dexamethasone (IC50NF‑κB = 0.005 ± 0.001 μM) and no transactivation activity. B53 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, B53 is able to significantly relieve dermatitis on a mouse model via
oral drug intervention.