(+)-(2r,5s)-4-[4-cyano-3-(Trifluoromethyl)phenyl]-2,5-dimethyl-n-[6-(Trifluoromethyl)pyridin-3- Yl]piperazine-1-carboxamide (Ym580) As an Orally Potent and Peripherally Selective Nonsteroidal Androgen Receptor Antagonist.
From: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. isao.kinoyama@jp.astellas.com
Journal of medicinal chemistry
- Publish Date: Jan 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 2
- Pages: 716-26
- Medium: Print
- Language: English
- Citation (JAMA): Kinoyama Isao, Taniguchi Nobuaki, Toyoshima Akira, et al. (+)-(2r,5s)-4-[4-cyano-3-(Trifluoromethyl)phenyl]-2,5-dimethyl-n-[6-(Trifluoromethyl)pyridin-3- Yl]piperazine-1-carboxamide (Ym580) As an Orally Potent and Peripherally Selective Nonsteroidal Androgen Receptor Antagonist.. J. Med. Chem. Jan 2006;49:716-26
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 Headings (Keywords): Administration, Oral, Androgen Antagonists, Animals, Antineoplastic Agents, CHO Cells, Cricetinae, Cricetulus, Humans, Hypothalamus, Male, Organ Size, Piperazines, Prostate, Pyridines, Rats, Receptors, Androgen, Stereoisomerism, Structure-Activity Relationship, Testosterone, Tissue Distribution, Transcription, Genetic
Check for Full Text / PubMed Unique Identifier (PMID): 16420057
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