Endocrine properties of the testosterone 5α-reductase inhibitor turosteride (FCE 26073)

Abstract

Turosteride was tested in a series of studies for its effect on 5α-reductase and for its possible influence on other steroidogenic enzymes and on steroid receptors. The compound was found to inhibit human and rat prostatic 5α-reductases with IC 50 values of 55 and 53 nM, respectively, whereas it caused a less marked inhibition of the dog enzyme (IC 50 2.2 μM). Turosteride showed no relevant effect on rat adrenal C 20,22-desmolase (IC 50 254 μM) and human placental aromatase (IC 50 > 100 μM), and only at relatively high concentrations it caused inhibition of human placental 5-ene-3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD-I) (IC 50 2.5 μM). Turosteride was found to be a selective 5α-reductase inhibitor showing no noteworthy binding to receptors for androgens (relative binding affinity, RBA, 0.004%) estrogens (⩽ 0.005%), progesterone (< 0.005%), glucocorticoids (< 0.01%) and mineralocorticoids (< 0.03%). Its biochemical profile was similar to that of finasteride, whereas 4-MA (17 β- N, N-diethyl-carbamoyl-4-methyl-4-aza-5 α-androstan-3-one) was confirmed to be a non-selective 5α-reductase inhibitor, showing a degree of binding affinity to the androgen receptor (RBA 0.1%) and a marked inhibition of 3β-HSD-I (IC 50 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 IC 50 values of ≈ 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.