No abstract

The chemical synthesis and structure-activity relationships of a novel series of 17beta-glucocorticoid butyrolactones possessing either a 16alpha,17alpha-isopropylidene or -butylidene group are described. The sulfur-linked gamma-lactone group was incorporated onto the 17beta-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 (t1/2 = 4-5 min) in the case of lactones possessing a sulfur atom in the alpha-position of the butyrolactone group, whereas carbon-linked lactones were stable in plasma. 16alpha,17alpha-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 beta-position were more potent glucocorticoid agonists than those linked through the alpha-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.

A series of novel pregnane derivatives bearing γ-butyrolactones at C21 were prepared and tested as glucocorticoid agonists. The compounds were also tested for their lability in human plasma, and found to be rapidly hydrolysed by the enzyme paraoxonase to the respective hydroxyacids.

Novel Glucocorticoid Antedrugs Possessing a 21-(γ-Lactone) Ring. -A series of novel lactone-containing pregnanes such as (VIII) and (IXb)-(IXf) as well as their 1,2-dihydro analogues are synthesized and tested as glucocorticoid agonists. -(ANGELL, RICHARD M.; BIGGADIKE, KEITH; FARRELL, ROSANNE M.; FLACK, STEPHEN S.; HANCOCK, ASHLEY P.; IRVING, WENDY R.; LYNN, SEAN M.; PROCOPIOU, PANAYIOTIS A.; J.