Anti-inflammatory 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma.
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.
Ashton
M J
MJ
Dagenham Research Centre, Rhône-Poulenc Rorer Central Research, Essex,U.K.
Lawrence
C
C
Karlsson
J A
JA
Stuttle
K A
KA
Newton
C G
CG
Vacher
B Y
BY
Webber
S
S
Withnall
M J
MJ
D000731:Androstanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D002460:Cell Line; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009929:Organ Size; D011654:Pulmonary Edema / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014444:Tyrosine Transaminase / Q000096:biosynthesis
D000731:Androstanes; D011965:Receptors, Glucocorticoid; D014444:Tyrosine Transaminase