Novel Glucocorticoid Antedrugs Possessing a 17β-(γ-Lactone) Ring

The chemical synthesis and structure−activity relationships of a novel series of 17β-glucocorticoid butyrolactones possessing either a 16α,17α-isopropylidene or -butylidene group are described. The sulfur-linked γ-lactone group was incorporated onto the 17β-position of the androstane nucleus via Barton ester decarboxylation and trapping the generated 17-radical with butyrolactone disulfides. The glucocorticoid butyrolactones were hydrolyzed in human plasma by the enzyme paraoxonase to the respective hydroxy acids, which were very weak glucocorticoid agonists. The rate of hydrolysis in plasma was very rapid (t 1/2 = 4−5 min) in the case of lactones possessing a sulfur atom in the α-position of the butyrolactone group, whereas carbon-linked lactones were stable in plasma. 16α,17α-Butylidenes were more potent glucocorticoid agonists than the corresponding 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 β-position were more potent glucocorticoid agonists than those linked through the α-position of the lactone. The most potent compounds were also shown to be stable in human lung S9 fraction, showed much lower systemic effects than budesonide in the thymus involution test, and possessed topical antiinflammatory activity in the rat ear edema model.