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

Venkatesh D. Handratta, Danijela Jelovac, Brian J. Long, Ritesh Kataria, Ivo P. Nnane, Vincent C.O. Njar, Angela M.H. Brodie

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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-(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× 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.

Original languageEnglish (US)
Pages (from-to)155-165
Number of pages11
JournalJournal of Steroid Biochemistry and Molecular Biology
Issue number3
StatePublished - Oct 2004
Externally publishedYes


  • Androgens
  • Antitumor efficacy
  • CYP17 inhibitors
  • Pharmacokinetics
  • Prostate cancer therapy
  • Synthesis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology


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