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 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.

• Authors: Venkatesh D Handratta, Danijela Jelovac, Brian J Long, Ritesh Kataria, Ivo P Nnane, Vincent C O Njar, Angela M H Brodie
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 92 Issue 3 Pg. 155-65 (Oct 2004) ISSN: 0960-0760 [Print] England
• PMID: 15555909 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 3-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene
• 3-hydroxy-17-(imidazol-1-yl)androsta-5,16-diene
• Androstadienes
• Androstanols
• Imidazoles
• Triazoles
• Finasteride
• Steroid 17-alpha-Hydroxylase

Topics

• Androstadienes (pharmacokinetics, pharmacology)
• Androstanols (pharmacokinetics, pharmacology)
• Animals
• Chromatography, High Pressure Liquid
• Dose-Response Relationship, Drug
• Finasteride (pharmacology)
• Humans
• Imidazoles (pharmacokinetics, pharmacology)
• Male
• Mice
• Mice, SCID
• Prostatic Neoplasms (drug therapy, enzymology)
• Steroid 17-alpha-Hydroxylase (antagonists & inhibitors)
• Time Factors
• Transplantation, Heterologous
• Triazoles (pharmacokinetics, pharmacology)