Novel glucocorticoid antedrugs possessing a 17 beta-(gamma-lactone) ring

The chemical synthesis and structure-activity relationships of a novel seri es of 17 beta -glucocorticoid butyrolactones possessing either a 16 alpha , 17 alpha -isopropylidene or -butylidene group are described. The sulfur-lin ked gamma -lactone group was incorporated onto the 17 beta -position of the androstane nucleus via Barton ester decarboxylation and trapping the gener ated 17-radical with butyrolactone disulfides. The glucocorticoid butyrolac tones were hydrolyzed in human plasma by the enzyme paraoxonase to the resp ective hydroxy acids, which were very weak glucocorticoid agonists. The rat e of hydrolysis in plasma was very rapid (t(1/2) = 4-5 min) in the case of lactones possessing a sulfur atom in the alpha -position of the butyrolacto ne group, whereas carbon-linked lactones were stable in plasma. 16 alpha ,1 7 alpha -Butylidenes were more potent glucocorticoid agonists than the corr esponding isopropylidene derivatives. Similarly, 1,4-dien-3-ones were more potent than the corresponding 4-en-3-ones. The butyrolactones linked to the steroidal nucleus via the beta -position were more potent glucocorticoid a gonists than those linked through the a-position of the lactone. The most p otent compounds were also shown to be stable in human lung S9 fraction, sho wed much lower systemic effects than budesonide in the thymus involution te st, and possessed topical antiinflammatory activity in the rat ear edema mo del.