VN-851

The pharmacokinetics of several new androgen synthesis inhibitors were investigated after intravenous administration in mice. The inhibitors were: 3beta-hydroxy-17-(1 H-imidazol-1-yl)androsta-5,16-diene (VN/85-1), 3beta-hydroxy-17-(1 H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1), 17-(1 H-imidazol-1-yl)androsta-4,16-diene-3-one (VN/108-1) and 17-(5'-isoxazolyl)androsta-4,16-dien-3-one (L-39).

Male Balb/c mice were injected with VN/85-1, VN/87-1, VN/108-1 or L-39 at 10, 25 and 50 mg/kg doses. Blood was collected at various times after drug administration via the eye orbit. The concentrations of VN/85-1, VN/87-1, VN/108-1 or L-39 in plasma were analyzed by a reversed-phase HPLC method with UV detection.

The plasma levels of VN/85-1, VN/87-1, VN/108-1 and L-39 declined biexponentially with terminal elimination half-lives ranging from 0.88 to 1.77 h. The terminal half-lives for VN/87-1, VN/85-1 and VN/108-1 were similar. However, the terminal half-life for L-39 was significantly longer than those for VN/87-1, VN/85-1 and VN/108-1. The systemic clearance values for the steroids ranged from 0.85 to 10.91 l/h per kg with a rank order of their clearance of L-39>VN/87-1>VN/108-1>VN/85-1. The apparent volumes of distribution at steady state for the steroids ranged from 0.58 to 18.85 l/kg with a rank order of their apparent V(ss) of L-39>VN/87-1>VN/85-1>VN/108-1. The clearance and apparent V(ss) for all four compounds were dose-independent following intravenous administration of doses up to 50 mg/kg.

VN/85-1, VN/87-1, VN/108-1 and L-39 are rapidly cleared from the systemic circulation and display linear pharmacokinetics in mice. The information presented may be used to improve the disposition profiles and activities of the steroidal inhibitors of androgen synthesis in animal models of prostate cancer.

17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit potent noncompetitive inhibition of human 17alpha-hydroxylase/C17,20-lyase with IC50 values ranging from 7 to 90 nM, and Ki 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 (Ki of 1.2 nM) and 7 nM (Ki of 1.9 nM), respectively. VN/107-1, VN/108-1 and VN/109-1 also showed moderate inhibition of 5alpha-reductase in human prostatic microsomes. Normal adult male rats were treated 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 administered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotestosterone (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% compared to the control group. Similarly, the concentration of DHT in the serum and prostates was significantly (p<0.05) diminished in rats treated with the 17-azolyl steroids by 39-80% compared to the control group. Furthermore, the wet weights of the prostates and seminal vesicles were significantly (p<0.05) reduced by several of the novel steroids. Although only one dose 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 research and development of suitable agents for the treatment of androgen dependent prostate cancer.