Development of Nuclear Receptor Modulators

  • Simone Schierle
  • Daniel MerkEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1824)


With 49 members identified thus far, the superfamily of nuclear receptors offers a large number of targets to be pharmacologically exploited. Some nuclear receptors already look back to a successful history as drug targets, while others still lack any identified ligand. The development of small molecules targeting nuclear receptor is a challenging task and has to consider not only high affinity binding but also aspects as the nuclear localization of the target protein or transactivation efficacy. In this chapter, we summarize characteristics of nuclear receptors as target family, strategies of hit and lead identification, and the variety of methods for in vitro characterization of nuclear receptor modulators. A detailed method chapter describes an example optimization of a nuclear receptor modulator as well as hybrid reporter gene assays as a very flexible method of choice for in vitro characterization. Thereby, the chapter provides an introduction to nuclear receptor ligand development.

Key words

Nuclear receptors Transactivation assay Reporter gene assay Farnesoid X receptor Medicinal chemistry Drug discovery 


  1. 1.
    Aranda A, Pascual A (2001) Nuclear hormone receptors and gene expression. Physiol Rev 81(3):1269–1304CrossRefPubMedGoogle Scholar
  2. 2.
    Germain P, Chambon P, Eichele G et al (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58(4):712–725CrossRefPubMedGoogle Scholar
  3. 3.
    Evans RM, Mangelsdorf DJ (2014) Nuclear receptors, RXR, and the big bang. Cell 157(1):255–266. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Germain P, Chambon P, Eichele G et al (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58(4):760–772. CrossRefPubMedGoogle Scholar
  5. 5.
    de Lera AR, Bourguet W, Altucci L, Gronemeyer H (2007) Design of Selective Nuclear Receptor Modulators: RAR and RXR as a case study. Nat Rev Drug Discov 6(10):811–820. CrossRefPubMedGoogle Scholar
  6. 6.
    Nuclear Receptors Nomenclature Committee (1999) A unified nomenclature system for the nuclear receptor superfamily. Cell 97(2):161–163. CrossRefGoogle Scholar
  7. 7.
    Germain P, Staels B, Dacquet C et al (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58(4):685–704. CrossRefPubMedGoogle Scholar
  8. 8.
    Merk D, Steinhilber D, Schubert-Zsilavecz M (2012) Medicinal chemistry of Farnesoid X receptor ligands: from agonists and antagonists to modulators. Future Med Chem 4(8):1015–1036. CrossRefPubMedGoogle Scholar
  9. 9.
    Proschak E, Heitel P, Kalinowsky L, Merk D (2017) Opportunities and challenges for fatty acid Mimetics in drug discovery. J Med Chem 60(13):5235–5266. CrossRefPubMedGoogle Scholar
  10. 10.
    Pellicciari R, Passeri D, De Franco F et al (2016) Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-Cholan-24-Oic acid (TC-100), a novel bile acid as potent and highly selective FXR agonist for Enterohepatic disorders. J Med Chem 59(19):9201–9214. CrossRefGoogle Scholar
  11. 11.
    Costantino G, Macchiarulo A, Entrena-Guadix A et al (2003) Binding mode of 6ECDCA, a potent bile acid agonist of the Farnesoid X receptor (FXR). Bioorg Med Chem Lett 13(11):1865–1868. CrossRefPubMedGoogle Scholar
  12. 12.
    Pellicciari R, Fiorucci S, Camaioni E et al (2002) 6α-ethyl-Chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with Anticholestatic activity. J Med Chem 45(17):3569–3572. CrossRefGoogle Scholar
  13. 13.
    Merk D, Steinhilber D, Schubert-Zsilavecz M (2014) Characterizing ligands for Farnesoid X receptor-available in vitro test Systems for Farnesoid X Receptor Modulator Development. Expert Opin Drug Discov 9(1):27–37. CrossRefPubMedGoogle Scholar
  14. 14.
    Flesch D, Cheung S-Y, Schmidt J et al (2017) Non-acidic Farnesoid X receptor modulators. J Med Chem 60(16):7199–7205. CrossRefPubMedGoogle Scholar
  15. 15.
    Achenbach J, Gabler M, Steri R et al (2013) Identification of novel Farnesoid X receptor modulators using a combined ligand- and structure-based virtual screening. MedChemComm 4(6):920. CrossRefGoogle Scholar
  16. 16.
    Merk D, Gabler M, Gomez RC et al (2014) Anthranilic acid derivatives as novel ligands for Farnesoid X receptor (FXR). Bioorg Med Chem 22(8):2447–2460. CrossRefPubMedGoogle Scholar
  17. 17.
    Merk D, Lamers C, Ahmad K et al (2014) Extending the structure-activity relationship of anthranilic acid derivatives as Farnesoid X receptor modulators: development of a highly potent partial Farnesoid X receptor agonist. J Med Chem 57(19):8035–8055. CrossRefPubMedGoogle Scholar
  18. 18.
    Merk D, Lamers C, Weber J et al (2015) Anthranilic acid derivatives as nuclear receptor modulators—development of novel PPAR selective and dual PPAR/FXR ligands. Bioorg Med Chem 23(3):499–514. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Pharmaceutical ChemistryGoethe University FrankfurtFrankfurtGermany

Personalised recommendations