Androstene-17-thioketals. 1st communication: glucocorticoid receptor binding, antiproliferative and antiinflammatory activities of some novel 20-thiasteroids (androstene-17-thioketals).
The unique replacements of the alpha-hydroxyl and beta-ketol groups of corticoids at C17 with selected, simple alkylthio or (2-fluoroalkyl)thio groups resulted in the structurally novel steroids, C17-alkylthioketals of 9 alpha-fluoro-11 beta-hydroxy-androsta-1,4-diene-3,17-dione. The described androstene-17-thioketals (20-thiasteroids) had high affinities for the glucocorticoid receptor protein of rat liver cytosol. Most were more potent than triamcinolone acetonide, a clinically moderately potent corticoid, in antiproliferative and antiinflammatory activities in mice. Specifically, (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-11 beta-hydroxy-17-(methylthio) androsta-1,4-dien-3-one (tipredane, SQ 27,239) and (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-17-[2-(fluoroethyl)thio] - 11 beta - hydroxy-androsta-1,4-dien-3-one (SQ 28,300), topically applied, were as potent as halcinonide, a clinically highly potent corticoid, in inhibition of croton oil-induced edema in the mouse. It is suggested that both thiasteroids could be moderately to highly potent topical antiinflammatory agents in man.
D000315:Adrenalectomy; D000736:Androstenes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D003436:Croton Oil; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D051379:Mice; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
D000736:Androstenes; D000893:Anti-Inflammatory Agents; D011965:Receptors, Glucocorticoid; D003436:Croton Oil; D004247:DNA