PYRIDYL SUBSTITUTED BENZOCYCLOALKENES - NEW INHIBITORS OF 17-ALPHA-HYDROXYLASE - 17,20-LYASE (P450 17-ALPHA)

Compounds capable of inhibiting 17alpha-hydroxylase / 17,20-lyase (P450 17alpha) are of great interest for the therapy of prostatic cancer since they block androgen biosynthesis. In order to evaluate the inhibitory activity of a series of benzocycloalkenes developed in our group, an in vitro assay was established using rat testicular microsomes - source of the enzyme, non labelled progesterone as substrate and a HPLC procedure for separation of the steroids. The inhibitory activities of 33 test compounds were compared to ketoconazole (IC50 67 muM), a known inhibitor of P450 17alpha, which recently has been successfully used in prostate cancer patients. Several compounds of the present study were stronger inhibitors of P450 17alpha than ketoconazole. The most active compounds were compound 12(5-methoxy-2-(4-pyridylmethyl)-1-tetralone: IC50 13 muM) and compound 13(5-methoxy-2-(4-pyridyl)-1-tetralone: IC50 13 muM).