title: Indazole estrogens: highly selective ligands for the estrogen receptor beta.
abstract: The estrogen receptors, ERalpha and ERbeta, are important pharmaceutical targets. To develop ERbeta-selective ligands, we synthesized a series of nonsteroidal compounds having a phenyl-2H-indazole core with different groups at C-3. Several of these show high affinity and good ERbetaselectivity, especially those with polar and/or polarizable substituents at this site (halogen, CF(3), nitrile); the best compounds have affinities for ERbeta comparable to estradiol, with ERbetaaffinity selectivity >100. This potency and ERbeta selectivity is also seen in cell-based transcriptional assays, where several compounds showed ERbeta efficacies equivalent to that of estradiol with ERbeta potency selectivities of 100. These compounds might prove useful as selective pharmacological probes to study the biological actions of estrogens mediated through ERbeta, and they might lead to the development of useful pharmaceuticals. These findings also contribute to an evolving pharmacophore that characterizes certain nonsteroidal ligands having high ERbeta subtype affinity and potency selectivity.
authors.affiliation: Department of Chemistry, University of Illinois, 600 South Matthews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Fabio
authors.initials: F
authors.lastname: Stossi
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carlson
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D001667:Binding, Competitive; D045744:Cell Line, Tumor; D047629:Estrogen Receptor beta / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D047629:Estrogen Receptor beta; D007093:Imidazoles; D008024:Ligands