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

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1948-1959
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number6
DOIs
Publication statusPublished - 2014 Mar 15
Externally publishedYes

Keywords

  • Inverse agonist
  • Retinoic acid receptor-related orphan receptor
  • Silicon

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors'. Together they form a unique fingerprint.

Cite this