Anti-inflammatory 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma

J Med Chem. 1996 Dec 6;39(25):4888-96. doi: 10.1021/jm9604639.


The synthesis and anti-inflammatory potencies of a new class of 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compounds from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17beta-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compounds with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17beta-thioalkyl-16alpha,17alpha-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.

MeSH terms

  • Androstanes / chemistry
  • Androstanes / metabolism
  • Androstanes / pharmacology
  • Androstanes / therapeutic use*
  • Animals
  • Asthma / drug therapy*
  • Cell Line
  • Humans
  • Liver / cytology
  • Liver / drug effects
  • Liver / enzymology
  • Magnetic Resonance Spectroscopy
  • Male
  • Organ Size
  • Pulmonary Edema / prevention & control
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucocorticoid / metabolism
  • Structure-Activity Relationship
  • Thymus Gland / drug effects
  • Thymus Gland / metabolism
  • Thymus Gland / pathology
  • Tyrosine Transaminase / biosynthesis


  • Androstanes
  • Receptors, Glucocorticoid
  • Tyrosine Transaminase