ERbeta ligands. Part 5: synthesis and structure-activity relationships of a series of 4'-hydroxyphenyl-aryl-carbaldehyde oxime derivatives.
A series of 4'-hydroxyphenyl-aryl-carbaldehyde oximes (5b) was prepared and found to have high affinity (4nM) and modest selectivity (39-fold) for estrogen receptor-beta (ERbeta). Substitution of one of the core rings of the scaffold based around these novel ligands further expanded our knowledge in the quest toward achieving high affinity and selectivity for ERbeta. An X-ray co-crystal of structure 11 revealed that the oxime moiety was mimicking the C-ring of genistein, as previously predicted by SAR and docking studies.
Mewshaw
Richard E
RE
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. mewshar@wyeth.com
Bowen
S Marc
SM
Harris
Heather A
HA
Xu
Zhang B
ZB
Manas
Eric S
ES
Cohn
Stephen T
ST
D000447:Aldehydes / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D047629:Estrogen Receptor beta / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D008958:Models, Molecular; D010091:Oximes / Q000138:chemical synthesis* / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000447:Aldehydes; D047629:Estrogen Receptor beta; D007202:Indicators and Reagents; D008024:Ligands; D010091:Oximes; D020845:Selective Estrogen Receptor Modulators