Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus.
A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.
Salvati
Mark E
ME
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. mark.salvati@bms.com
Balog
Aaron
A
Wei
Donna D
DD
Pickering
Dacia
D
Attar
Ricardo M
RM
Geng
Jieping
J
Rizzo
Cheryl A
CA
Hunt
John T
JT
Gottardis
Marco M
MM
Weinmann
Roberto
R
Martinez
Rogelio
R
D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D011944:Receptors, Androgen