Next Article in Journal
Different Myosin Head Conformations in Bony Fish Muscles Put into Rigor at Different Sarcomere Lengths
Next Article in Special Issue
Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility
Previous Article in Journal
Using Spectral Representation to Classify Proteins’ Conformational States
Previous Article in Special Issue
Update on FXR Biology: Promising Therapeutic Target?
Open AccessArticle

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(7), 2090;
Received: 25 June 2018 / Revised: 13 July 2018 / Accepted: 17 July 2018 / Published: 18 July 2018
(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)
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. View Full-Text
Keywords: phenanthridinone; steroid surrogate; antagonist phenanthridinone; steroid surrogate; antagonist
Show Figures

Graphical abstract

MDPI and ACS Style

Nishiyama, Y.; Fujii, S.; Makishima, M.; Hashimoto, Y.; Ishikawa, M. Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton. Int. J. Mol. Sci. 2018, 19, 2090.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Search more from Scilit
Back to TopTop