title: Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.
abstract: The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.
authors.affiliation: Discovery Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Esther Y H
authors.initials: EY
authors.lastname: Chao
authors.forename: Jon L
authors.initials: JL
authors.lastname: Collins
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gaillard
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Orband-Miller
authors.forename: Robert T
authors.initials: RT
authors.lastname: Nolte
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: William J
authors.initials: WJ
authors.lastname: Zuercher
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C490917:ESRRG protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D013629:Tamoxifen