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

Compounds capable of inhibiting 17alpha-hydroxylase / 17,20-lyase (P45 0 17alpha) are of great interest for the therapy of prostatic cancer s ince they block androgen biosynthesis. In order to evaluate the inhibi tory activity of a series of benzocycloalkenes developed in our group, an in vitro assay was established using rat testicular microsomes - s ource of the enzyme, non labelled progesterone as substrate and a HPLC procedure for separation of the steroids. The inhibitory activities o f 33 test compounds were compared to ketoconazole (IC50 67 muM), a kno wn inhibitor of P450 17alpha, which recently has been successfully use d in prostate cancer patients. Several compounds of the present study were stronger inhibitors of P450 17alpha than ketoconazole. The most a ctive compounds were compound 12(5-methoxy-2-(4-pyridylmethyl)-1-tetra lone: IC50 13 muM) and compound 13(5-methoxy-2-(4-pyridyl)-1-tetralone : IC50 13 muM).