2. Academic Validation
  3. Discovery of a subnanomolar and selective spirocyclic agonist of the glucocorticoid receptor

Discovery of a subnanomolar and selective spirocyclic agonist of the glucocorticoid receptor

  • Eur J Med Chem. 2019 Jan 1:161:354-363. doi: 10.1016/j.ejmech.2018.10.032.
Eduard Badarau 1,  Frédéric Robert 2,  Stéphane Massip 3,  Florian Jakob 4,  Simon Lucas 4,  Daniela Friebe 4,  Stephanie Hennen 4,  Sven Frormann 4,  Léon Ghosez 5
Affiliations

Affiliations

  • 1 Univ. Bordeaux, European Institute of Chemistry and Biology (IECB), 2 Rue Robert Escarpit, 33607, Pessac, France; Univ. Bordeaux, Institute of Chemistry & Biology of Membranes & Nano-objects (CBMN), Allée Geoffroy Saint Hilaire, Bât B14, 33600, Pessac, France.
  • 2 Univ. Bordeaux, Institute of Molecular Sciences (ISM), Bâtiment A12, 351 cours de la Libération, 33405, TALENCE Cedex, France.
  • 3 Univ. Bordeaux, European Institute of Chemistry and Biology (IECB), 2 Rue Robert Escarpit, 33607, Pessac, France.
  • 4 Grunenthal GmbH, Zieglerstr. 6, 52078, Aachen, Germany.
  • 5 Univ. Bordeaux, European Institute of Chemistry and Biology (IECB), 2 Rue Robert Escarpit, 33607, Pessac, France. Electronic address: l.ghosez@iecb.u-bordeaux.fr.
PMID: 30384041 DOI: 10.1016/j.ejmech.2018.10.032
Abstract

Pure diastereomeric spirocyclic analogs of fluorocortivazol were conveniently prepared by a short and efficient synthetic sequence recently developed in our laboratory. The structures and conformations of several key products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. Biological evaluation led to the identification of a highly potent hGR agonist with excellent anti-inflammatory effects in the subnanomolar range. All tested compounds from this series were also selective versus the Progesterone Receptor.

Keywords

Fluorocortivazol; Glucocorticoids; Spirocyclic analogues; hGR agonist.

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