Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists.
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.
Salvati
Mark E
ME
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. mark.salvati@bms.co
Balog
Aaron
A
Shan
Weifang
W
Rampulla
Richard
R
Giese
Soren
S
Mitt
Tom
T
Furch
Joseph A
JA
Vite
Gregory D
GD
Attar
Ricardo M
RM
Jure-Kunkel
Maria
M
Geng
Jieping
J
Rizzo
Cheryl A
CA
Gottardis
Marco M
MM
Krystek
Stanley R
SR
Gougoutas
Jack
J
Galella
Michael A
MA
Obermeier
Mary
M
Fura
Aberra
A
Chandrasena
Gamini
G
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
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