The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2571-7. doi: 10.1016/j.bmcl.2014.03.070. Epub 2014 Apr 2.

Abstract

We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.

Keywords: Glucocorticoid receptor; Indazoles; Inhalation; Non-steroidal selective glucocorticoid receptor modulators.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • High-Throughput Screening Assays
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Receptors, Glucocorticoid / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Ligands
  • Receptors, Glucocorticoid
  • Sulfonamides