Abstract
A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.
MeSH terms
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Administration, Oral
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Androgen Antagonists / adverse effects
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Androgen Antagonists / chemical synthesis*
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Androgen Antagonists / pharmacology
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Androgen Receptor Antagonists*
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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CHO Cells
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Cricetinae
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Cricetulus
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Humans
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Hypothalamus / metabolism
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Male
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Organ Size / drug effects
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Prostate / anatomy & histology
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Prostate / drug effects
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Prostate / metabolism
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Rats
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Receptors, Androgen / genetics
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Stereoisomerism
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Structure-Activity Relationship
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Testosterone / blood
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Tissue Distribution
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Transcription, Genetic
Substances
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4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-N-(6-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxamide
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Androgen Antagonists
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Androgen Receptor Antagonists
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Antineoplastic Agents
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Piperazines
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Pyridines
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Receptors, Androgen
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Testosterone