Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors

Hirozumi Toyama, Masaharu Nakamura, Masahiko Nakamura, Yotaro Matsumoto, Madoka Nakagomi, Yuichi Hashimoto

研究成果: Article査読

14 被引用数 (Scopus)

抄録

Retinoic acid receptor (RAR)-related orphan receptors (RORs) regulate a variety of physiological processes, including hepatic gluconeogenesis, lipid metabolism, circadian rhythm and immune function. The RAR agonist: all-trans retinoic acid was reported to be an RORβ inverse agonist, but no information is available regarding ROR activity of its synthetic analogue Am580. Therefore, we screened Am580 and some related tetramethyltetrahydronaphthalene derivatives and carried out structural development studies, including substitution of carbon atoms with silicon, with the aim of creating a potent ROR transcriptional inhibitor. The phenyl amide disila compound 22 showed the most potent ROR-inhibitory activity among the compounds examined. Its activity towards RORα, RORβ and RORγ was increased compared to that of Am580. The IC50 values for RORα, RORβ and RORγ are 1.3, >10 and 4.5 μM, respectively.

本文言語English
ページ(範囲)1948-1959
ページ数12
ジャーナルBioorganic and Medicinal Chemistry
22
6
DOI
出版ステータスPublished - 2014 3月 15
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬科学
  • 創薬
  • 臨床生化学
  • 有機化学

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