Phenethyl pyridines with non-polar internal substitutents as selective ligands for estrogen receptor beta

To create estrogen receptor beta (ERO)-selective ligands with improved biological characteristics, we have extended our investigations of structurally simple bibenzyl-core ligands by preparing a series of compounds in which one phenol is replaced by a 3-hydroxypyridine ring. These phenethyl pyridines were obtained by picoline anion alkylation, and compounds with different patterns of alkyl substitution on the central two carbon units were prepared. Binding affinities for ER alpha and ER beta were determined, and ligands with promising affinities and selectivities for ER beta were further tested for their gene transcriptional activity. Several compounds had high affinity selectivity and good potency selectivity in transcription assays. This study advances our understanding of compounds having ER-subtype selectivity and will help to direct efforts in developing novel ER ligands. (C) 2009 Elsevier Masson SAS. All rights reserved.