4-PREGNENE-3-ONE-20-BETA-CARBOXALDEHYDE - A POTENT INHIBITOR OF 17-ALPHA-HYDROXYLASE/C17,20-LYASE AND OF 5-ALPHA-REDUCTASE

The pregnene derivative, 4-pregnene-3-one-20-beta-carboxaldehyde (22-A) was evaluated as an inhibitor of 17-alpha-hydroxylase/C17,20-lyase in rat testicular microsomes and of 5-alpha-reductase in human prostatic homogenates. The effect of the compound in vivo was studied in adult male rats. The 22-A demonstrated potent and competitive inhibition of 17-alpha-hydroxylase and C17,20-lyase with K(i) values 8.48 and 0.41-mu-M, respectively, significantly below the K(m) values for these two enzymes (33.75 and 4.55-mu-M). This compound also showed potent inhibition of 5-alpha-reductase with a K(i) value of 15.6 nM (K(m) for this enzyme is 50 nM). By comparison, ketoconazole, a currently studied 17-alpha-hydroxylase/C17,20-lyase inhibitor for the treatment of prostatic cancer, showed less potent inhibition of 17-alpha-hydroxylase (K(i) 39.5-mu-M) and C17,20-lyase (K(i) 3.6-mu-M) and did not inhibit 5-alpha-reductase. Progesterone which has been reported to inhibit the 17-alpha-hydroxylase/C17,20-lyase, did not significantly reduce the production of testosterone by rat testes in vitro in comparison to controls, while the same concentration of 22-A demonstrated a 42% reduction of testosterone biosynthesis. When the adult male rats were injected s.c. with 22-A at 50 mg/day/kg for a 2 week period, the testosterone concentrations in the rat sera were significantly lower than control values (P < 0.05), whereas serum corticosterone levels did not change. These results suggest that 22-A is a selective potent inhibitor for 17-alpha-hydroxylase and C17,20-lyase, but is more potent for the C17,20-lyase. The compound also inhibits 5-alpha-reductase, and therefore may reduce biosynthesis of testosterone and dihydrotestosterone effectively. Thus, 22-A may be useful in the treatment of problems associated with the androgen excess and prostatic cancer.