2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2014 May 1;22(9):2799-808. doi: 10.1016/j.bmc.2014.03.007.
Yuko Nishiyama 1,  Masahiko Nakamura 1,  Takashi Misawa 1,  Madoka Nakagomi 2,  Makoto Makishima 3,  Minoru Ishikawa 4,  Yuichi Hashimoto 1
Affiliations

Affiliations

  • 1 Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 Department of Biology, Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan.
  • 3 Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
  • 4 Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: m-ishikawa@iam.u-tokyo.ac.jp.
PMID: 24702856 DOI: 10.1016/j.bmc.2014.03.007
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.

Keywords

Inverse agonist; LXR; Phenanthridinone; ROR.

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