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

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Yamamoto S, Matsunaga N, Hitaka T, Yamada M, Hara T, Miyazaki J, Santou T, Kusaka M, Yamaoka M, Kanzaki N, Furuya S, Tasaka A, Hamamura K, Ito M

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. Epub 2011 Oct 28.

PubMed ID
22094279 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BicalutamideAndrogen receptorEC 50 (nM)>10000N/AN/ADetails
BicalutamideAndrogen receptorIC 50 (nM)330N/AN/ADetails
BicalutamideAndrogen receptorIC 50 (nM)54N/AN/ADetails
StanoloneAndrogen receptorIC 50 (nM)>10000N/AN/ADetails
StanoloneAndrogen receptorEC 50 (nM)6.2N/AN/ADetails
StanoloneAndrogen receptorIC 50 (nM)2.1N/AN/ADetails