Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases

J Med Chem. 2017 Oct 26;60(20):8591-8605. doi: 10.1021/acs.jmedchem.7b01215. Epub 2017 Oct 12.


A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

MeSH terms

  • Acetamides / therapeutic use*
  • Administration, Inhalation
  • Aged
  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Indazoles / therapeutic use*
  • Mass Spectrometry
  • Powders
  • Proton Magnetic Resonance Spectroscopy
  • Pulmonary Edema / drug therapy*
  • Rats
  • Receptors, Glucocorticoid / drug effects*


  • 2,2,2-trifluoro-N-(1-((1-(4-fluorophenyl)-1H-indazol-5-yl)oxy)-1-(3-methoxyphenyl)-2-propanyl)acetamide
  • Acetamides
  • Indazoles
  • Powders
  • Receptors, Glucocorticoid