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. 2018 Jul 18;19(7):2090.
doi: 10.3390/ijms19072090.

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

Free PMC article

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

Yuko Nishiyama et al. Int J Mol Sci. .
Free PMC article


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.

Keywords: antagonist; phenanthridinone; steroid surrogate.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Chemical structures of endogenous steroidal ligands for NRs and phenanthridinone ligands for target proteins that recognize endogenous steroidal ligands.
Scheme 1
Scheme 1
Reagents and conditions: (a) CF3COCF3·1.5H2O, p-TsOH·H2O, toluene, reflux, 27%; (b) 2-iodobenzoic acid, EDC, DMAP, DMF, 100 °C; (c) SEMCl, NaH, DMF, 0 °C to RT; (d) Pd(OAc)2, PCy3·HBF4, Cs2CO3, DMA, 130 °C, 24% in 2 steps; (e) TBAF, THF, reflux, 18%.
Figure 2
Figure 2
Chemical structures of AR antagonists.

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