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

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 long and winding road: defining the biological role and clinical importance of paraoxonases

“…The enzyme has been shown to inactivate lactone derivatives of glucocorticoids (85). This has been exploited to limit unwanted side-effects of such drugs during topical application by neutralising any drug diffusing outside the area under treatment.…”

Retrometabolism‐Based Drug Design and Targeting

“…A higher metabolic stability of such structures in lung tissues than in corresponding plasma has been independently confirmed [206]. The rate of hydrolysis was also rapid in plasma for the 17-linked lactones possessing a sulfur in the a-position of the butyrolactone group (t 1/2 < 5 min), whereas Clinked lactones were stable [208]. Among the compounds of this series, 50 showed promising topical antiinflammatory activity in the rat ear edema model and much lower systemic effects than budesonide in the thymus involution test.…”

“…In patients with asthma or seasonal rhinitis, itrocinonide administered as a dry powder formulation did exert some antiasthmatic and antirhinitic efficacy, but these effects were not sufficient enough to compete with the efficacy of current inhaled steroids [206]. Glucocorticoid g-Lactones A group at GlaxoSmithKline has explored a series of various glactone derivatives including 21-thio derivatives of fluocinolone acetonide with g-lactones and cyclic carbonates (e.g., 49) [207] and sulfur-linked g-lactones incorporated at the 17b-position (e.g., 50) [208]. For these compounds, human serum paraoxonase (E.C.…”

Regioselective Spiroannulations of α‐Acetyl Lactones

“…Examples range from terpenoid lactones, such as canangone (1), [2] which often exhibit remarkable antifeedant activities, [3] to pharmaceutically important steroids, [4] such as the well-known diuretic aldosterone antagonist, spironolactone (2) (Scheme 1). [5] Scheme 1.…”