Pharmacology of novel steroidal inhibitors of cytochrome P45017α (17α-hydroxylase/C17–20 lyase)

SE Barrie, GA Potter, PM Goddard, BP Haynes… - The Journal of steroid …, 1994 - Elsevier
SE Barrie, GA Potter, PM Goddard, BP Haynes, M Dowsett, M Jarman
The Journal of steroid biochemistry and molecular biology, 1994Elsevier
Medical or surgical castration for the treatment of prostatic cancers prevents androgen
production by the testes, but not by the adrenals. Inhibition of the key enzyme for androgen
biosynthesis, cytochrome P45017α, could prevent androgen production from both sources.
The in vivo effects of 17-(3-pyridyl) androsta-5, 16-dien-3β-ol (CB7598) and 17-(3-pyridyl)
androsta-5, 16-dien-3-one (CB7627), novel potent steroidal inhibitors of this enzyme, on
WHT mice were compared with those of castration and two clinically active compounds …
Medical or surgical castration for the treatment of prostatic cancers prevents androgen production by the testes, but not by the adrenals. Inhibition of the key enzyme for androgen biosynthesis, cytochrome P45017α, could prevent androgen production from both sources. The in vivo effects of 17-(3-pyridyl)androsta-5,16-dien-3β-ol (CB7598) and 17-(3-pyridyl)androsta-5,16-dien-3-one (CB7627), novel potent steroidal inhibitors of this enzyme, on WHT mice were compared with those of castration and two clinically active compounds, ketoconazole and flutamide. Flutamide and surgical castration caused significant reductions in the weights of the ventral prostate and seminal vesicles. CB7598, in its 3β-O-acetate form (CB7630), and CB7627 caused significant reductions in the weights of the ventral prostate, seminal vesicles, kidneys and testes when administered once daily for 2 weeks. Ketoconazole, given on the same schedule, caused no reductions. Plasma testosterone was reduced to ⩽0.1 nM by CB7630, despite a 3- to 4-fold increase in the plasma level of luteinizing hormone. Adrenal weights were unchanged following treatment with CB7630 or CB7627 but were markedly increased following ketoconazole, indicating no inhibition of corticosterone production by these steroidal compounds. These results indicate that CB7598, CB7630 or CB7627 may be useful in the treatment of hormone-dependent prostatic cancers.
Elsevier