Androstene-17-thioketals. 2nd communication: pharmacological profiles of tipredane and (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-17-[2-(fluoroethyl)thio]-11 beta-hydroxy-androsta-1,4-dien-3-one, structurally novel 20-thiasteroids possessing potent and selective topical antiinflammatory activity.
Two structurally novel alkylthio-substituted steroids, (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-11 beta-hydroxy-17-(methylthio)andro-1,4-dien-3-one (tipredane, SQ 27,239) and (11 beta, 17 alpha)-(ethylthio)-9 alpha-fluoro-17-[2-(fluoroethyl) thio]-11 beta-hydroxy-androsta-1,4-dien-3-one (SQ 28,300) were compared to presently available topical corticosteroids for in vitro and in vivo glucocorticoid and antiinflammatory activities. Based upon results of in vitro assays, in vivo antiinflammatory tests in mice, and human vasoconstriction measurements, the thiasteroids most closely resemble moderately potent to highly potent corticoids. These compounds display more modest activity in topical antiinflammatory assays using rats. Both tipredane and SQ 28,300 exhibit favorable separation of local antiinflammatory activity from systemic effects on thymus and hypothalamic-pituitary-adrenal axis function, most probably due to rapid metabolic inactivation. As such, these compounds represent potentially safer therapy for topical treatment of corticoid-responsive skin diseases and bronchopulmonary conditions in humans.
D000287:Administration, Topical; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents; D004247:DNA / Q000096:biosynthesis; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006003:Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008901:Mineralocorticoids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D008901:Mineralocorticoids; D011965:Receptors, Glucocorticoid; C051756:tipredane; C051757:SQ 28300; D006003:Glycogen; D004247:DNA