Synthesis and Evaluation of Azole‐Substituted Tetrahydronaphthalenes as Inhibitors of P450 arom, P450 17, and P450 TxA2

In search of potential drugs for the treatment of estrogen‐ and androgen‐dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH3 substituent at the benzene nucleus and an imidazol‐4‐yl, imidazol‐1‐yl, or 1,2,4‐triazol‐1‐yl substituent in 2‐position were synthesized with and without C1‐spacer between the rings (compounds 2 – 26). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA2 (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA2 inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin‐primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene‐induced tumor; pre‐ and postmenopausal model).

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