ENDOCRINE PROPERTIES OF THE TESTOSTERONE 5-ALPHA-REDUCTASE INHIBITOR TUROSTERIDE (FCE-26073)

Turosteride was tested in a series of studies for its effect on 5alpha-reductase and for its possible influence on other steroidogenic enzymes and on steroid receptors. The compound was found to inhibit human and rat prostatic 5alpha-reductases with IC50 values of 5S and 53 nM, respectively, whereas it caused a less marked inhibition of the dog enzyme (IC50 2.2 muM). Turosteride showed no relevant effect on rat adrenal C-20-desmolase, C-22-desmolase, (IC50 254 muM) and human placental aromatase (IC50 > 100 muM), and only at relatively high concentrations it caused inhibition of human placental 5-ene-3beta-hydroxysteroid dehydrogenase-isomerase (3beta-HSD-I) (IC50 2.5 muM). Turosteride was found to be a selective 5alpha-reductase inhibitor showing no noteworthy binding to receptors for androgens (relative binding affinity, RBA, 0.004%), estrogens (less-than-or-equal-to 0.005%), progesterone (<0.005%), glucocorticoids (<0.01%) and mineralocorticoids (<0.03%). Its biochemical profile was similar to that of finasteride, whereas 4-MA (17beta-N,N-diethyl-carbamoyl-4-methyl-4-aza-5alpha-androstan-3-one) was confirmed to be a non-selective 5alpha-reductase inhibitor, showing a degree of binding affinity to the androgen receptor (RBA 0.1%) and a marked inhibition of 3beta-HSD-1 (IC50 32 nM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, turosteride reduced the ventral prostate and seminal vesicle growth promoting effect of TP, with IC50 values of almost-equal-to 5 and 6.7 mg/kg/day, whereas levator ani weight was unchanged. In comparison, 4-MA was approx. 3-fold less potent than turosteride in reducing the prostate and seminal vesicle weights and caused a marked reduction of levator ani weight, thus showing its unselectivity.