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Bioorg Med Chem. 2012 Jan 1;20(1):422-34. doi: 10.1016/j.bmc.2011.10.067. Epub 2011 Oct 28.

Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.

Author information

1
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Yamamoto_Satoshi@takeda.co.jp

Abstract

A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

PMID:
22094279
DOI:
10.1016/j.bmc.2011.10.067
[Indexed for MEDLINE]

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