title: Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.
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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Yamamoto_Satoshi@takeda.co.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Takenori
authors.initials: T
authors.lastname: Hitaka
authors.forename: Masami
authors.initials: M
authors.lastname: Yamada
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
authors.forename: Junichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Santou
authors.forename: Masami
authors.initials: M
authors.lastname: Kusaka
authors.forename: Masuo
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Furuya
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tasaka
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Hamamura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ito
mesh_terms: D019943:Amino Acid Substitution; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009154:Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D011758:Pyrroles; D011944:Receptors, Androgen