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

• DOI: 10.1021/jm001035c
• Publication Date: 2002-07-26T04:53:54Z
• Authors: Panayiotis A. Pro...; Keith Biggadike; Alan F. English; Rosanne M. Farrell; Graham N. Hagger; Ashley P. Hancock; Michael V. Haase; Wendy R. Irving; Meenu Sareen; Michael A. Snowden; Yemisi E. Solanke; Cathy J. Tralau-S...; Sarah E. Walton; Jenny A. Wood
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

The chemical synthesis and structure-activity relationships of a novel series 17beta-glucocorticoid butyrolactones possessing either 16alpha,17alpha-isopropylidene or -butylidene group are described. sulfur-linked gamma-lactone was incorporated onto the 17beta-position androstane nucleus via Barton ester decarboxylation trapping generated 17-radical with butyrolactone disulfides. glucocorticoid were hydrolyzed in human plasma by enzyme paraoxonase to respective hydroxy acids, which very weak agonists. rate hydrolysis rapid (t1/2 = 4-5 min) case lactones sulfur atom alpha-position group, whereas carbon-linked stable plasma. 16alpha,17alpha-Butylidenes more potent agonists than corresponding isopropylidene derivatives. Similarly, 1,4-dien-3-ones 4-en-3-ones. linked steroidal beta-position those through lactone. most compounds also shown be lung S9 fraction, showed much lower systemic effects budesonide thymus involution test, possessed topical antiinflammatory activity rat ear edema model.