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. Epub 2018 Oct 15.

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.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Quantum Theory
  • Receptors, Glucocorticoid / agonists*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Receptors, Glucocorticoid
  • Spiro Compounds