Discovery of Novel Nonsteroidal SGRMs of Sulfonamide-2-Oxo-Tetrahydroquinoline Derivatives by Carbonyl Migration

Glucocorticoids
(GCs) are limited by severe side effects, driving
the development of selective glucocorticoid receptor modulators (SGRMs)
with improved therapeutic profiles. We previously development the
SGRM lead B53, which suffered from poor metabolic stability.
In this study, structure-guided optimization of B53 yielded
43 novel sulfonamide derivatives. Among them, D8, which
contained 2-oxo-tetrahydroquinoline by carbonyl migration form B53, manifests an excellent SGRM with remarkable transrepression
potency (IC50NF‑κB = 0.9 nM) superior to dexamethasone
(IC50 NF‑κB = 5.0 nM). Besides, D8 exhibits a significantly higher specificity for GR over
AR, MR, and PR and exhibited less adverse effects on osteoprotegerin.
Furthermore, D8 demonstrated improved metabolic stability
and optimized binding mode within the GR LBD. In vivo, oral administration of D8 significantly alleviated
dermatitis and autoimmune hepatitis in mouse models, underscoring
its therapeutic potential and validating our design strategy.