Ashton M J, Lawrence C, Karlsson J A, Stuttle K A, Newton C G, Vacher B Y, Webber S, Withnall M J
Dagenham Research Centre, Rhône-Poulenc Rorer Central Research, Essex,U.K.
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.
描述了一类新型17β-硫代烷基-16α,17α-缩酮和缩醛雄甾烷的合成及其抗炎效力。这类新型甾体化合物是通过将相应17-酸的2-硫代-1,2-二氢吡啶-1-基酯断裂为17-自由基而制得的。所产生的自由基用各种亲核二硫化物捕获，得到在C-16和C-17处具有缩醛或缩酮官能团以及在C-17处具有硫醚键的甾体D环。该系列化合物与糖皮质激素受体具有高亲和力，并且通过它们在体外大鼠肝细胞系中诱导酪氨酸转氨酶活性的能力来衡量，它们是功能性激动剂。当直接经气道给药时，这些17β-硫代烷基雄甾烷能有效抑制葡聚糖诱导的大鼠肺部炎症。与目前可用的吸入性糖皮质激素相比，高局部效力以及低诱导全身性糖皮质激素样副作用（大鼠胸腺萎缩）的倾向，使本发明的化合物具有高度的气道选择性。本文所述的17β-硫代烷基-16α,17α-缩酮雄甾烷可用于治疗诸如哮喘等炎性疾病。
