Pyridyl Substituted Benzocycloalkenes: New Inhibitors of 17α-Hydroxylase/ 17,20-Lyase (P450 17α)

Abstract

Compounds capable of inhibiting 17α-hydroxylase / 17,20-lyase (P450 17α) 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 as 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 μM), a known inhibitor of P450 17a, which recently has been successfully used in prostate cancer patients. Several compounds of the present study were stronger inhibitors of P450 17 α than ketoconazole. The most active compounds were compound 12(5-methoxy-2-(4-pyridylmethyl)-1-tetralone: 1C₅₀ 13 μM) and compound 13(5-methoxy-2-(4-pyridyl)-1-tetralone: IC₅₀ 13 μM).

Key Words: :

• inhibitors of 17α-hydroxylase / 17,20-lyase (P450 17α)
• androgen dependent prostate carcinoma
• pyridyl substituted benzocycloalkenes
• in vitro assay
• HPLC