EVALUATION OF SOME 4-FLUORO AND 4-CYANO DERIVATIVES OF DELTA(4),3-KETOSTEROIDS AS INHIBITORS OF TESTOSTERONE 5-ALPHA-REDUCTASE

Some 4-fluorinated analogues of 3-oxo-Delta(4) steroids and 4-cyano derivatives of progesterone and androstenedione were evaluated as inhibitors of steroid ja-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 mu M), while 4-cyanoprogesterone was a potent inhibitor of both the rat and human enzymes (IC50 values = 0.045 mu M and 0.050 mu M 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.