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The C(17,20)-lyase and 5alpha-reductase are key enzymes in the biosynthesis of androgens. The effects of novel steroidal compounds were evaluated as inhibitors against both human C(17,20)-lyase and 5alpha-reductase in vitro. The concentrations of testosterone (T) and dihydrotestosterone (DHT) in the prostate, testis and serum and changes in the tissue weights were also determined in rats treated with the novel inhibitors. L-12 and L-26 showed potent inhibition of human testicular C(17,20)-lyase with IC50 values of 50 and 25 nM, respectively. L-12, L-38, and I-47 showed moderate inhibition of human testicular C(17,20)-lyase with IC50 values of 75, 108, and 70 nM, respectively similar to ketoconazole (78 nM). Interestingly, L-6, L-26, and L-38 also showed some inhibitory activity against 5alpha-reductase with IC50 values of 75, 125, and 377 nM, respectively. Finasteride, an inhibitor of 5alpha-reductase had an IC50 value of 33 nM. However, ketoconazole did not inhibit 5alpha-reductase nor did finasteride inhibit C(17,20)-lyase. Treatment of normal male rats with several of these novel inhibitors (50 mg/kg x day, s.c., for 14 consecutive days) caused about 45-91% decrease in serum, testicular and prostatic T concentration. Similarly, serum and prostatic DHT concentration were significantly decreased in rats treated with these novel compounds by 50-90% compared with controls. Surgical castration caused almost complete elimination of circulating T and DHT concentration in rat tissues. L-6 and L-12 were the most effective and reduced the wet weight of the prostate by 50%. Although future improvements in their bioavailability are necessary, these novel steroidal compounds show promise as potential agents for reducing T and DHT levels in patients with androgen dependent diseases.

Inhibition of Androgen Synthesis in Human Testicular and Prostatic Microsomes and in Male Rats by Novel Steroidal Compounds*