Effects of novel 17-azolyl compounds on androgen synthesis in vitro and invivo

17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit pot ent noncompetitive inhibition of human 17 alpha-hydroxylase/C-17,C-20-lyase with IC50 values ranging from 7 to 90 nM, and K-i values from 1.2 to 41 nM . VN/85-1 and VN/108-1 were the most potent inhibitors against this enzyme with IC50 value of 8 nM (K-i of 1.2 nM) and 7 nM (K-i of 1.9 nM), respectiv ely. VN/107-1, VN/108-1 and VN/109-1 also showed moderate inhibition of Scc -reductase in human prostatic microsomes. Normal adult male rats were treat ed with these novel 17-azolyl steroidal compounds at a dose level of 50 mg/ kg, s.c., for 14 consecutive days, sacrificed 1-2 h after the last administ ered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotesto sterone (DHT) were measured. Tissue T levels were significantly (p < 0.05) lower in rats treated with the novel 17-azolyl steroids by more than 50% co mpared to the control group. Similarly, the concentration of DHT in the ser um and prostates was significantly (p < 0.05) diminished in rats treated wi th the 17-azolyl steroids by 39-80% compared to the control group. Furtherm ore, the wet weights of the prostates and seminal vesicles were significant ly (p < 0.05) reduced by several of the novel steroids. Although only one d ose was evaluated in these studies, VN/85-1 was the most effective compound and reduced prostatic androgen levels by more than 80% and the wet weights of the prostate and seminal vesicles in rats by about 50%. These findings suggest that these novel compounds may provide useful leads for the researc h and development of suitable agents for the treatment of androgen dependen t prostate cancer. (C) 2000 Published bl, Elsevier Science Ltd. All rights reserved.