Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 5: Combined A- and C-ring structure–activity relationship studies

Benzopyrans are selective estrogen receptor (ER) β agonists (SERBAs), which bind the ER subtypes α and β in opposite orientations. Here we describe the synthesis of a late stage intermediate that allowed us to combine A-ring and C-ring modifications and carry out simultaneous SAR studies at both positions. Modification of both positions proved additive, maintaining affinity and improving ERβ selectivity up to 83-fold. An X-ray cocrystal structure confirms the previously observed binding mode in ERβ.

Graphical abstractCombined A/C-ring structure–activity relationship studies on the benzopyran scaffold.Figure optionsDownload full-size imageDownload as PowerPoint slide