title: Novel glucocorticoid antedrugs possessing a 17beta-(gamma-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.
authors.affiliation: Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. pap1746@glaxowellcome.uk
authors.forename: P A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: K
authors.initials: K
authors.lastname: Biggadike
authors.forename: A F
authors.initials: AF
authors.lastname: English
authors.forename: R M
authors.initials: RM
authors.lastname: Farrell
authors.forename: G N
authors.initials: GN
authors.lastname: Hagger
authors.forename: A P
authors.initials: AP
authors.lastname: Hancock
authors.forename: M V
authors.initials: MV
authors.lastname: Haase
authors.forename: W R
authors.initials: WR
authors.lastname: Irving
authors.forename: M
authors.initials: M
authors.lastname: Sareen
authors.forename: M A
authors.initials: MA
authors.lastname: Snowden
authors.forename: Y E
authors.initials: YE
authors.lastname: Solanke
authors.forename: C J
authors.initials: CJ
authors.lastname: Tralau-Stewart
authors.forename: S E
authors.initials: SE
authors.lastname: Walton
authors.forename: J A
authors.initials: JA
authors.lastname: Wood
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004487:Edema / Q000188:drug therapy; D005938:Glucocorticoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008297:Male; D009929:Organ Size; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000033:anatomy & histology / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D002087:Butyrates; D005938:Glucocorticoids; D007783:Lactones; D011965:Receptors, Glucocorticoid