The hit-to-lead optimization of 1,2,3,4,4a,9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists

The structure–activity relationship (SAR) study of a 1,2,3,4,4a,9a-hexahydro-1H-xanthene series of selective, human glucocorticoid receptor α (hGRα) antagonists is reported. Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays. Four different regions of the scaffold were modified to assess the effects on hGRα antagonism and related potency. Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a, as well as an improved chemical stability, which make it a promising lead for the subsequent optimization.

A small, non-steroidal molecule, GR antagonist 1a, was identified during a high-throughput screening (HTS) campaign. Following the hit-to-lead optimization, its allyl derivative 8d was obtained as a novel glucocorticoid receptor antagonist.Figure optionsDownload as PowerPoint slide