Structure-activity relationship-guided development of retinoic acid receptor-related orphan receptor gamma (RORγ)-selective inverse agonists with a phenanthridin-6(5H)-one skeleton from a liver X receptor ligand

Yuko Nishiyama, Masahiko Nakamura, Takashi Misawa, Madoka Nakagomi, Makoto Makishima, Minoru Ishikawa, Yuichi Hashimoto

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Retinoic acid receptor-related orphan receptors (RORs), which belong to the nuclear receptor superfamily, regulate many physiological processes, including hepatic gluconeogenesis, lipid metabolism, immune function and circadian rhythm. Since RORs resemble liver X receptors (LXRs) in the fold structure of their ligand-binding domains, we speculated that ROR-mediated transcription might be modulated by LXR ligands, in line with the multi-template hypothesis. Therefore, we screened our LXR ligand library for compounds with ROR ligand activity and identified a novel ROR ligand with a phenanthridin-6(5H)-one skeleton. Structure-activity relationship studies aimed at separating ROR inverse agonistic activity from LXR-agonistic activity enabled us to develop a series of ROR inverse agonists based on the phenanthridin-6(5H)-one skeleton, including a RORγ-selective inverse agonist.

Original languageEnglish
Pages (from-to)2799-2808
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number9
DOIs
Publication statusPublished - 2014 May 1
Externally publishedYes

Keywords

  • Inverse agonist
  • LXR
  • Phenanthridinone
  • ROR

ASJC Scopus subject areas

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

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