A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.
A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
Henke
Brad R
BR
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA. brh14990@gsk.com
Consler
Thomas G
TG
Go
Ning
N
Hale
Ron L
RL
Hohman
Dana R
DR
Jones
Stacey A
SA
Lu
Amy T
AT
Moore
Linda B
LB
Moore
John T
JT
Orband-Miller
Lisa A
LA
Robinett
R Graham
RG
Shearin
Jean
J
Spearing
Paul K
PK
Stewart
Eugene L
EL
Turnbull
Philip S
PS
Weaver
Susan L
SL
Williams
Shawn P
SP
Wisely
G Bruce
GB
Lambert
Millard H
MH
D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D011960:Receptors, Estrogen; D014227:Triazines