title: 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.affiliation: Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201-1559, USA.
authors.forename: Venkatesh D
authors.initials: VD
authors.lastname: Handratta
authors.forename: Danijela
authors.initials: D
authors.lastname: Jelovac
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Long
authors.forename: Ritesh
authors.initials: R
authors.lastname: Kataria
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Nnane
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
authors.forename: Angela M H
authors.initials: AM
authors.lastname: Brodie
mesh_terms: D000730:Androstadienes / Q000493:pharmacokinetics* / Q000494:pharmacology; D000732:Androstanols / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C439677:3-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene; C495960:3-hydroxy-17-(imidazol-1-yl)androsta-5,16-diene; D000730:Androstadienes; D000732:Androstanols; D007093:Imidazoles; D014230:Triazoles; D018120:Finasteride; D013254:Steroid 17-alpha-Hydroxylase