Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity

A novel series of selective ligands for the human glucocorticoid receptor is described. Structure–activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-α secretion model. Compound 28 had an ED50 of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.

Graphical abstractCompound 28 was found to have a dissociated glucocorticoid profile in vitro and produced a dose-dependent anti-inflammatory response in an in vivo mouse model.Figure optionsDownload full-size imageDownload as PowerPoint slide