Anti-inflammatory 17β-Thioalkyl-16α,17α-ketal and -acetal Androstanes: A New Class of Airway Selective Steroids for the Treatment of Asthma

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Abstract
The synthesis and anti-inflammatory potencies of a new class of 17β-thioalkyl-16α,17α-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 17β-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 17β-thioalkyl-16α,17α-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.