Potent CYP17 inhibitors: improved syntheses, pharmacokinetics and anti-tumor activity in the LNCaP human prostate cancer model

Abstract

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 100 mg/kg of VN/85-1, peak plasma level of 16.73 μg/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-(1 H-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× dose regimen) of VN/85-1 was more effective than a once daily dose. In contrast, 3× 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.