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 androg en-dependent cancer as well as the prophylaxis of metastases, tetralon es, tetralins, and dihydronaphthalenes bearing a OCH3 substituent, at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-tria zol-1-yl substituent in 2-position were synthesized with and without C -1-spacer between the rings (compounds 2-26). The compounds were teste d in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA(2) (citrated human whole blood). To examine selectivity, some comp ounds mere further tested in vitro for inhibition of P450 IS (bovine a drenal mitochondria), P450 sec (bovine adrenal mitochondria) and corti coid formation (aldosterone, corticosterone; ACTH stimulated rat adren al tissue). In vitro, selected compounds were examined in Sprague Dawl ey rats regarding P450 TxA(2) inhibition, reduction of plasma testoste rone concentration, antiuterotrophic activity (inhibition of the utero trophic activity of androstenedione), reduction of plasma estradiol co ncentration (pregnant ;mares' serum gonadotropin-primed rats), and mam mary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre-and postmenopausal model). In the series of imidazol-4-yl compound s, which represent a novelty in the field of azole inhibitors of stero idogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 w ere found: 7-OCH3-2-(imidazol-4-ylmethylene)-1-tetralone (4) and 7-OCH 3-2-(imidazol-4-ylmethyl)-tetralin (12) are among the most potent inhi bitors of P450 arom in vitro known so far. Compound 4 is a selective i nhibitor, whereas 12 shows in addition strong inhibition of P450 17. I n contrast to 12, the 6-OCH3 derivative (compound 11) is a selective i nhibitor of P450 17, being 50 times more potent than ketoconazole. Som e imidazol-1-yl compounds show a marked inhibition of P450 TxA(2): 2-( imidazol-1-ylmethyl)-1-tetralone (13) is a selective inhibitor of P450 TxA(2), whereas 7-OCH3-2-(imidazo)-1-ylmethyl)-tetralin (17) as well as 2-(imidazol-1-ylmethyl)-tetralin (16) and 7-OCH3-2-imidazol-1-yl-3, 4'-dihydronaphthalene (25) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as w ell as corticosterone formation, the compounds show only little inhibi tory activity. Aldosterone formation, however, is inhibited at low con centrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit a ldosterone synthesis less than the well known inhibitor of P450 arom f adrozole. The compounds show activity in the aforementioned in vivo te sts.