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

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

  • Bioorg Med Chem. 2012 Jan 1;20(1):422-34. doi: 10.1016/j.bmc.2011.10.067.
Satoshi Yamamoto 1,  Nobuyuki Matsunaga,  Takenori Hitaka,  Masami Yamada,  Takahito Hara,  Junichi Miyazaki,  Takashi Santou,  Masami Kusaka,  Masuo Yamaoka,  Naoyuki Kanzaki,  Shuichi Furuya,  Akihiro Tasaka,  Kazumasa Hamamura,  Mitsuhiro Ito
Affiliations

Affiliation

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Yamamoto_Satoshi@takeda.co.jp
PMID: 22094279 DOI: 10.1016/j.bmc.2011.10.067
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.

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