title: Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes.
abstract: In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with Ki values reaching the sub-nanomolar range (Ki=0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC50=0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Andrea
authors.initials: A
authors.lastname: De Cupertinis
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.forename: Barbara
authors.initials: B
authors.lastname: Bargagli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Gunther
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
mesh_terms: D004305:Dose-Response Relationship, Drug; D047629:Estrogen Receptor beta / Q000819:agonists*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D047629:Estrogen Receptor beta; D010091:Oximes; C005704:salicylaldoxime