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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| Published in | Chemical & Pharmaceutical Bulletin Vol. 56; no. 11; pp. 1555 - 1561 |
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| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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TOKYO
The Pharmaceutical Society of Japan
01.11.2008
Pharmaceutical Society of Japan Pharmaceutical Soc Japan Japan Science and Technology Agency |
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| Abstract | 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). |
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| AbstractList | 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). 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=130nM) with no agonistic activity even at 10000nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7mg/kg). Prostate cancer is the most common cancer amongst men and the second most common malignant cause of male death after lung cancer in the U.S1). Since the growth of prostate cancer is dependent on androgen, androgen receptor (AR) antagonists such as flutamide (1), a precursor of its active form hydroxyflutamide (2), and bicalutamide (3) are currently used as hormone therapy (Chart 1)2). These antiandrogens exhibit good efficacy in many cases and comprise an important part of effective therapeutics3-6). However, a considerable problem with these antiandrogens is that recurrence occurs after a short period of response7). They have partial agonistic activities at high concentration in vitro8), which may attribute to recurrence. |
| Author | Nakagawa, Toshito Sato, Haruhiko Kawata, Hiromitsu Onuma, Etsuro Ishikura, Nobuyuki Taniguchi, Kenji Tsunenari, Toshiaki Imaoka, Ikuhiro Nakamura, Mitsuaki Tachibana, Kazutaka Ohta, Masateru Saito, Hidemi Nagamuta, Masahiro Shiraishi, Takuya Takanashi, Kenji Yoshino, Hitoshi |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/18981605$$D View this record in MEDLINE/PubMed |
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| Keywords | CELLS SIDE-CHAIN FLUTAMIDE ADVANCED PROSTATE-CANCER BICALUTAMIDE pure antagonist prostate cancer androgen receptor ANTIANDROGEN BEARING LIGAND ACETATE CASODEX |
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| Snippet | The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their... |
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| SubjectTerms | 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 |
| Title | Discovery of an Orally-Active Nonsteroidal Androgen Receptor Pure Antagonist and the Structure–Activity Relationships of Its Derivatives |
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