Abstract

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.