title: Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists.
abstract: A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.
authors.affiliation: Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. mark.salvati@bms.co
authors.forename: Mark E
authors.initials: ME
authors.lastname: Salvati
authors.forename: Aaron
authors.initials: A
authors.lastname: Balog
authors.forename: Weifang
authors.initials: W
authors.lastname: Shan
authors.forename: Richard
authors.initials: R
authors.lastname: Rampulla
authors.forename: Soren
authors.initials: S
authors.lastname: Giese
authors.forename: Tom
authors.initials: T
authors.lastname: Mitt
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Furch
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.forename: Jieping
authors.initials: J
authors.lastname: Geng
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Rizzo
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.forename: Jack
authors.initials: J
authors.lastname: Gougoutas
authors.forename: Michael A
authors.initials: MA
authors.lastname: Galella
authors.forename: Mary
authors.initials: M
authors.lastname: Obermeier
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
mesh_terms: D000284:Administration, Oral; D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014105:Tosyl Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C529326:(3aS-(3aalpha,4beta,5beta,7beta,7aalpha))-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile; C410798:AR protein, human; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D054833:Isoindoles; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide