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.
Subject(s)
Androgen Receptor Antagonists , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Isoindoles/pharmacology , Prostatic Neoplasms/drug therapy , Administration, Oral , Androgen Antagonists/pharmacology , Anilides/pharmacology , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Chromatography, High Pressure Liquid , Drug Design , Humans , Isoindoles/chemical synthesis , Isoindoles/pharmacokinetics , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Nitriles/pharmacology , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology , Protein Binding , Receptors, Androgen/metabolism , Structure-Activity Relationship , Tosyl Compounds/pharmacology , Tumor Cells, CulturedABSTRACT
Stille coupling under standard carbonylative conditions proceeds in poor yield when using hindered alkenylstannane and enol triflate partners. The inclusion of 35 mol % CuI or CuBr significantly improves the efficiency of the coupling, providing a variety of complex 1,4-dien-3-ones in good to excellent yield.
