title: Evaluation of some 4-fluoro- and 4-cyano derivatives of delta 4,3-ketosteroids as inhibitors of testosterone 5 alpha-reductase.
abstract: Some 4-fluorinated analogues of 3-oxo-delta 4 steroids and 4-cyano derivatives of progesterone and androstenedione were evaluated as inhibitors of steroid 5 alpha-reductase activity. Inhibitors of this enzyme may be useful in treating prostatic cancer. 4-Fluoroandrostenedione was a modest inhibitor of the rat enzyme (IC50 = 4.08 microM), while 4-cyanoprogesterone was a potent inhibitor of both the rat and human enzymes (IC50 values = 0.045 microM and 0.050 microM respectively). These two steroids were tested in vivo for activity against androgen sensitive organs in WHT mice. 4-Fluoroandrostenedione caused increases in organ weights, suggesting it is an androgen agonist, while the 4-cyano compound displayed modest androgen ablation. Therefore substitutions at the 4-position may produce compounds of therapeutic use in treating prostate cancer.
authors.affiliation: Drug Development Section, CRC Laboratory, Sutton, Surrey, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jarman
authors.forename: S E
authors.initials: SE
authors.lastname: Barrie
authors.forename: J
authors.initials: J
authors.lastname: Houghton
authors.forename: M G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: J
authors.initials: J
authors.lastname: Mann
authors.forename: M
authors.initials: M
authors.lastname: Haase-Held
authors.forename: M
authors.initials: M
authors.lastname: Hatzis
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D007536:Isomerism; D007664:Ketosteroids / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011374:Progesterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012669:Seminal Vesicles / Q000187:drug effects
chemical_list: C093699:4-cyanoprogesterone; D058891:5-alpha Reductase Inhibitors; D007664:Ketosteroids; D000735:Androstenedione; D011374:Progesterone; C093698:4-fluoroandrostenedione; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase