Inhibition of androgen synthesis by 22‐hydroximino‐23,24‐bisnor‐4‐cholen‐3‐one

The 22‐hydroximino‐23,24‐bisnor‐4‐cholen‐3‐one (22‐oxime) was synthesized and evaluated as an inhibitor of 17α‐hydroxylase/C 17,20 ‐lyase in rat testicular microsomes and the 5α‐reductase of human prostatic microsomes from patients with benign prostatic hypertrophy. The 22‐oxime demonstrated moderate inhibition for the 17α‐hydroxylase (Ki 74 nM vs. Km 29 nM) with progesterone as substrate and potent inhibition (Ki 18 nM vs. Km 76 nM) for the C 17,20 ‐lyase activity with 17α‐hydroxyprogesterone as substrate. Further investigation of this enzyme with progesterone as substrate demonstrated the inhibition occurred mainly at the 17α‐hydroxylation step of the progesterone substrate. The 22‐oxime also demonstrated potent and competitive inhibition of 5α‐reductase in human prostatic microsomes (Ki 1.4 nM vs. Km 14 nM). When adult male rats were injected subcutaneously (sc) daily with 22‐oxime (50 mg/kg/day) for 21 days, the concentrations of serum and testicular testosterone were significantly reduced by 65% and 59%, respectively, in comparison to vehicle‐treated controls. Furthermore, both testosterone and DHT concentrations in rat prostatic tissue were significantly decreased by 60% and 44% compared to control tissue. Serum LH concentrations were unchanged in the 22‐oxime‐treated group compared to the control group. This indicates that the reduction in androgen concentrations in animals treated with this compound is not due to its influence on pituitary feedback mechanisms which result in reduced LH secretion. These results suggest that 22‐oxime is effective in reducing androgen synthesis through the inhibition of 17α‐hydroxylase, C 17,20 ‐lyase, and 5α‐reductase both in vitro and in vivo.