A facile preparation of azolyl steroids, VN/85-1 and VN/87-1 (potent inhibitors of CYP17) has been developed. This process without tedious chromatographic separations improved the overall yields from 55 and 45% to 70 and 65% for VN/85-1 and VN/87-1, respectively. Pharmacokinetic studies of VN/85-1 were conducted in male SCID mice. Following subcutaneous (s.c.) administration of 100mg/kg of VN/85-1, peak plasma level of 16.73 microg/ml occurred after 45 min, and the compound was cleared rapidly with a t(1/2) of 52.34 min. The bioavailability of VN/85-1 after s.c. administration was 83.0%. VN/85-1 was also rapidly metabolized to the corresponding 3-oxo-4-ene analog, 17-(1H-imidazol-1-yl)androsta-4,16-diene-3-one (VN/108-1). In our attempt to optimize the anti-tumor efficacy of these two CYP17 inhibitors, we studied their anti-tumor efficacies in male SCID mice bearing LNCaP tumor xenografts, utilizing various drug doses and drug scheduling. Three times a day dose regimen (3 x dose regimen) of VN/85-1 was more effective than a once daily dose. In contrast, 3 x dose regimen doses of VN/87-1 were less effective than the once daily dose. However, at their effective dosage regimes, VN/85-1 and VN/87-1 were each as effective as castration and more effective than finasteride or casodex, an anti-androgen used for prostate cancer (PC) therapy. For all of the treatments, there was a strong correlation between the tumor volumes and other associated parameters, such as, tumor weights, and serum testosterone (T) and PSA levels. These results indicate that VN/85-1 or VN/87-1 may be useful in the treatment of hormone-dependent prostate cancer.

01 Jun 2003·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

Pharmacokinetics of novel inhibitors of androgen synthesis after intravenous administration in mice

Q4 · MEDICINE

Article

Author: Ivo P. Nnane ; Vincent C. O. Njar ; Angela M. H. Brodie

PURPOSEThe 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).METHODSMale 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.RESULTSThe 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.CONCLUSIONSVN/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.

01 Dec 1999·The Journal of Steroid Biochemistry and Molecular BiologyQ2 · BIOLOGY

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

Q2 · BIOLOGY

Article

Author: V.C.O. Njar ; Y. Liu ; Q. Lu ; A.M.H. Brodie ; I.P. Nnane

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Cancer	Preclinical	US	-	-

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