Efficient lead finding, activity enhancement and preliminary selectivity control of nuclear receptor ligands bearing a phenanthridinone skeleton

Yuko Nishiyama, Shinya Fujii, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Background: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for clinical use. We anticipated that efficient lead finding and enhancement of activity toward nuclear receptors recognizing endogenous steroidal ligands might be achieved by exhaustive evaluation of a steroid surrogate library coupled with examination of structure-activity relationships (SAR). Method: We evaluated our library of RORs (retinoic acid receptor-related orphan receptors) inverse agonists and/or PR (progesterone receptor) antagonists based on the phenanthridinone skeleton for antagonistic activities toward liver X receptors (LXRs), androgen receptor (AR) and glucocorticoid receptor (GR) and examined their SAR. Results: Potent LXRβ, AR, and GR antagonists were identified. SAR studies led to a potent AR antagonist (IC50: 0.059 µM). Conclusions: Our approach proved effective for efficient lead finding, activity enhancement and preliminary control of selectivity over other receptors. The phenanthridinone skeleton appears to be a promising steroid surrogate.

Original languageEnglish
Article number2090
JournalInternational journal of molecular sciences
Volume19
Issue number7
DOIs
Publication statusPublished - 2018 Jul 18

Keywords

  • Antagonist
  • Phenanthridinone
  • Steroid surrogate

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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