Phenethyl pyridines with non-polar internal substituents as selective ligands for estrogen receptor beta.
To create estrogen receptor beta (ERbeta)-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 ERalpha and ERbeta were determined, and ligands with promising affinities and selectivities for ERbeta 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.
Waibel
Michael
M
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801, United States.
Kieser
Karen J
KJ
Carlson
Kathryn E
KE
Stossi
Fabio
F
Katzenellenbogen
Benita S
BS
Katzenellenbogen
John A
JA
D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D011725:Pyridines