TY - JOUR
T1 - Potent CYP17 inhibitors
T2 - Improved syntheses, pharmacokinetics and anti-tumor activity in the LNCaP human prostate cancer model
AU - Handratta, Venkatesh D.
AU - Jelovac, Danijela
AU - Long, Brian J.
AU - Kataria, Ritesh
AU - Nnane, Ivo P.
AU - Njar, Vincent C.O.
AU - Brodie, Angela M.H.
N1 - Funding Information:
This study made use of the NMR facility at the University of Maryland, Baltimore, which is supported with funds from the University of Maryland, the National Institutes of Health (RR10441; RR15741), and the National Science Foundation (DBI0115795). This work was supported by the NIH grant CA-27440 and funds from Genta Inc.
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
KW - Androgens
KW - Antitumor efficacy
KW - CYP17 inhibitors
KW - Pharmacokinetics
KW - Prostate cancer therapy
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=9144242015&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=9144242015&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2004.07.006
DO - 10.1016/j.jsbmb.2004.07.006
M3 - Article
C2 - 15555909
AN - SCOPUS:9144242015
SN - 0960-0760
VL - 92
SP - 155
EP - 165
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 3
ER -