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

Journal of Medicinal Chemistry
M J AshtonM J Withnall

Abstract

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.

References

Dec 1, 1994·British Journal of Clinical Pharmacology·A GrahnénA Ling-Andersson
Feb 1, 1993·Thorax·S Holgate

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Citations

Aug 5, 1999·Cellular Signalling·R R MattinglyI G Macara
Jul 4, 1998·Natural Product Reports·J R Hanson
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·I D KuntzP A Kollman
Nov 24, 2004·Bioorganic & Medicinal Chemistry·Ranju GuptaGulshan Kumar
Jul 9, 2020·The Journal of Organic Chemistry·Motohiro FujiuKenji Yamawaki

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