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

Abstract

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

Synthesis and Evaluation of Azole-substituted 2-Aryl-6-methoxy-3,4-dihydronaphthalenes and -naphthalenes as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17

“…Compounds 7a, 7b, 12a, 12b, 14a, 14b, 16a, and 16b were tested for inhibition of P450 17 using human testicular enzyme as well as progesterone as substrate (25 µM) employing the procedure recently described [20] . Tested at a concentration of 2.5 µM, the title compounds showed no inhibitory activity (7a, -19.6%, 7b, -13.5%, 12a, -10.2% and 12b, 3.9%, 14a, -4.0%, 14b, -9.9%, 16a, -4.6% and 16b, 2.8%).…”

Determination of 17α-hydroxylase-C17,20-lyase (P45017α) enzyme activities and their inhibition by selected steroidal picolyl and picolinylidene compounds

“…Further incubation techniques apply non-labelled substrate steroids. enzyme products in these methods can be either isolated by high performance liquid chromatography and detected by ultraviolet spectrophotometry [20,[34][35] or can be directly quantified by specific immunoassays [9]. Technologies based on quantification of radio-labelled steroidal enzyme products, nevertheless, are acknowledged superior to other methods in sense of both precision and qualitative identification.…”

Synthesis of Novel Oximes of 2-Aryl-6-methoxy-3,4-dihydronaphthalene and Their Evaluation as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17)

“…[10] The determination of enzyme inhibition was performed according to the same literature. The microsomes were incubated with excess progesterone as substrate (25 µM), NADPH (500 µM) and inhibitor (2.5 µM) in phosphate buffer (temperature: 32 °C, termination after 20 min by addition of 1N HCl).…”