Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ

The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERR gamma LBD confirms the molecular basis of the selectivity. (c) 2005 Elsevier Ltd. All rights reserved.