Discovery of an Orally-Active Nonsteroidal Androgen Receptor Pure Antagonist and the Structure–Activity Relationships of Its Derivatives

The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agon...

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Bibliographic Details
Published inChemical & Pharmaceutical Bulletin Vol. 56; no. 11; pp. 1555 - 1561
Main Authors Tachibana, Kazutaka, Imaoka, Ikuhiro, Shiraishi, Takuya, Yoshino, Hitoshi, Nakamura, Mitsuaki, Ohta, Masateru, Kawata, Hiromitsu, Taniguchi, Kenji, Ishikura, Nobuyuki, Tsunenari, Toshiaki, Saito, Hidemi, Nagamuta, Masahiro, Nakagawa, Toshito, Takanashi, Kenji, Onuma, Etsuro, Sato, Haruhiko
Format Journal Article
LanguageEnglish
Japanese
Published TOKYO The Pharmaceutical Society of Japan 01.11.2008
Pharmaceutical Society of Japan
Pharmaceutical Soc Japan
Japan Science and Technology Agency
Subjects
Androgen Antagonists - chemical synthesis
Androgen Antagonists - pharmacology
androgen receptor
Androgen Receptor Antagonists
Animals
Binding, Competitive - drug effects
Chemistry
Chemistry, Medicinal
Chemistry, Multidisciplinary
CHO Cells
Cricetinae
Cricetulus
Crystallography, X-Ray
Genes, Reporter - drug effects
HeLa Cells
Humans
Indicators and Reagents
Life Sciences & Biomedicine
Male
Mice
Mice, Inbred ICR
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Models, Molecular
Pharmacology & Pharmacy
Physical Sciences
prostate cancer
pure antagonist
Science & Technology
Seminal Vesicles - drug effects
Structure-Activity Relationship
Thiohydantoins - chemical synthesis
Thiohydantoins - pharmacology
CELLS
SIDE-CHAIN
FLUTAMIDE
ADVANCED PROSTATE-CANCER
BICALUTAMIDE
pure antagonist
prostate cancer
androgen receptor
ANTIANDROGEN
BEARING
LIGAND
ACETATE
CASODEX
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Summary:The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7 mg/kg).
ISSN:0009-2363
1347-5223
DOI:10.1248/cpb.56.1555