Structure-activity relationships of topically active steroids: the selection of fluticasone propionate

Although corticosteroids have long been known to be effective in the treatment of respiratory diseases, the wide range of unwanted side-effects with the systemic compounds prompted the development of safe, topically active analogues. Of these analogues, betamethasone 17-valerate, beclomethasone 17,21-dipropionate, budesonide, flunisolide and triamcinolone acetonide have been developed as aerosols for use in asthma and rhinitis with a great deal of success and very little detectable systemic activity. In attempts to avoid these minimal side-effects, further analogues were prepared. The steroid 17-carboxylates were extremely active topically when esterified, while the parent acids were inactive. Thus, it was possible that enzymic hydrolysis of the ester function would lead to systemic deactivation. The 17-carboxylate series was superseded by the corresponding carbothioates, particularly fluticasone propionate which showed unusually high topical anti-inflammatory activity in rodents but was almost inactive after oral administration. This lack of oral activity is attributed to hepatic first-pass metabolism to the corresponding 17-carboxylic acid, which is virtually inactive.