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
  • 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. [email protected]
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.