title: Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 3: synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification.
abstract: Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER subtypes alpha and beta in opposite orientations. Here we describe the syntheses of cyclopentanone and cyclohexanone intermediates for SAR studies of the C-ring on the benzopyran scaffold. Modification of the C-ring disrupts binding to ERalpha, thus improving ERbeta selectivity up to 100-fold. X-ray cocrystal structures confirm previously observed binding modes.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. t_richardson@lilly.com
authors.forename: Timothy I
authors.initials: TI
authors.lastname: Richardson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Dodge
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Durst
authors.forename: Lance A
authors.initials: LA
authors.lastname: Pfeifer
authors.forename: Jikesh
authors.initials: J
authors.lastname: Shah
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Jim D
authors.initials: JD
authors.lastname: Durbin
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Norman
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D003512:Cyclohexanones / Q000138:chemical synthesis* / Q000494:pharmacology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D047629:Estrogen Receptor beta / Q000819:agonists*; D006801:Humans; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D011485:Protein Binding; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D003512:Cyclohexanones; D003517:Cyclopentanes; D047629:Estrogen Receptor beta; D008024:Ligands; D020845:Selective Estrogen Receptor Modulators; C007201:cyclopentanone; C036468:cyclohexanone