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) beta agonists (SERBAs), which bind the ER subtypes alpha and beta 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 ERP selectivity up to 83-fold. An X-ray cocrystal structure confirms the previously observed binding mode in ER beta. (c) 2007 Elsevier Ltd. All rights reserved.