title: A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.
abstract: 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.
authors.affiliation: GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA. brh14990@gsk.com
authors.forename: Brad R
authors.initials: BR
authors.lastname: Henke
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Consler
authors.forename: Ning
authors.initials: N
authors.lastname: Go
authors.forename: Ron L
authors.initials: RL
authors.lastname: Hale
authors.forename: Dana R
authors.initials: DR
authors.lastname: Hohman
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Jones
authors.forename: Amy T
authors.initials: AT
authors.lastname: Lu
authors.forename: Linda B
authors.initials: LB
authors.lastname: Moore
authors.forename: John T
authors.initials: JT
authors.lastname: Moore
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Orband-Miller
authors.forename: R Graham
authors.initials: RG
authors.lastname: Robinett
authors.forename: Jean
authors.initials: J
authors.lastname: Shearin
authors.forename: Paul K
authors.initials: PK
authors.lastname: Spearing
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.forename: Philip S
authors.initials: PS
authors.lastname: Turnbull
authors.forename: Susan L
authors.initials: SL
authors.lastname: Weaver
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.forename: G Bruce
authors.initials: GB
authors.lastname: Wisely
authors.forename: Millard H
authors.initials: MH
authors.lastname: Lambert
mesh_terms: 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
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D011960:Receptors, Estrogen; D014227:Triazines