Development of nonsteroidal glucocorticoid receptor modulators based on...

N-Benzyl-N-(4-phenoxyphenyl)benzenesulfonamide derivatives were developed as a novel class of nonsteroidal glucocorticoid receptor (GR) modulators, which are promising drug candidates for treating immune-related disorders. Focusing on the similarity of the GR and progesterone receptor (PR) ligand-binding domain (LBD) structures, we adopted our recently developed PR antagonist 10 as a lead compound and synthesized a series of derivatives. We found that the N-(4-phenoxyphenyl)benzenesulfonamide skeleton serves as a versatile scaffold for GR antagonists. Among them, 4-cyano derivative 14m was the most potent, with an IC₅₀ value of 1.43μM for GR. This compound showed good selectivity for GR; it retained relatively weak antagonistic activity toward PR (IC₅₀ for PR: 8.00μM; 250-fold less potent than 10), but showed no activity toward AR, ERα or ERβ. Interestingly, the 4-amino derivative 15a exhibited transrepression activity toward NF-κB in addition to GR-antagonistic activity, whereas 14m did not. The structure-activity relationship for transrepression was different from that for GR-antagonistic activity. Computational docking simulations suggested that 15a might bind to the ligand-binding pocket of GR in a different manner from 14m. These findings open up new possibilities for developing novel nonsteroidal GR modulators with distinctive activity profiles.