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

Abstract

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 targets 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 P450 18 (bovine adrenal mitochondria), P450 scc (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vitro, 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). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found; 7-OCH3-2-(imidazol-4-ylmethylene)-1-tetralone (4) and 7-OCH3-2-(imidazol-4-ylmethyl)-tetralin (12) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12, the 6-OCH3 derivative (compound 11) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA2: 2-(imidazol-1-ylmethyl)-1-tetralone (13) is a selective inhibitor of P450 TxA2, whereas 7-OCH3-2-(imidazol-1-ylmethyl)-tetralin (17) as well 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 well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.

Nonsteroidal aromatase inhibitors: Recent advances

“…The most potent AI in the tetralone series was the 7-methoxy derivative of 2 (4), that showed high aromatase inhibiting potency (IC 50 ¼ 0.041 mM) and selectivity. 52 Indeed, the selectivity issue is extremely important in the AI class, due to the widespread presence in the organism of P450 systems, whose concomitant inhibition could cause serious problems of side toxicity. The tetraline series was developed by Hartmann et al starting from the promising results obtained with 2-(4-pyridyl)methyl derivatives.…”

“…Unfortunately, 4 and (þ)-5 shared a disappointing in vivo activity as determined from rat experimental breast tumor models. 52,53 The tetralinic skeleton was further varied by changing it into a quinolinic one, in order to pursue the goal of simultaneously blocking both aromatase and another enzyme active in tumor tissues, i.e., thromboxane A 2 synthase (TxA 2 ). The involvement of TxA 2 in the proliferation of tumor cells, 54 as well as the possibility to control the metastasis production by means of TxA 2 inhibitors 55 had been earlier demonstrated.…”

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

“…The enzyme in question is 17α-hydroxylase-C17,20-lyase (P450 17) which catalyzes the conversion of progesterone and pregnenolone into the androgens, androstenedione and dehydroepiandrosterone (DHEA), respectively [11,12] . Recently we have shown [6,13,14] that a dihydro-or tetrahydronaphthalene nucleus is able to give -after linkage with an N containing heterocycle such as imidazole, pyrazine, or pyridine -highly potent inhibitors of P450 17 (e.g., I and II, Chart 1 [6] ). While the heterocyclic N is complexing the heme iron of P450 17, the rest of the molecule interacts with the apoprotein moiety.…”

“…As an alternative to antiestrogen treatment [2] , highly potent inhibitors of estrogen biosynthesis have been developed recently, some of which already have been admitted to the market (fadrozole, anastrozole, letrozole) [3][4][5] . Efforts are currently being undertaken to develop inhibitors of androgen biosynthesis [6,7] , as alternatives to antiandrogens (flutamide, cyproterone acetate) [8,9] a n d GnRH analogs (such as busereline) [10] . The enzyme in question is 17α-hydroxylase-C17,20-lyase (P450 17) which catalyzes the conversion of progesterone and pregnenolone into the androgens, androstenedione and dehydroepiandrosterone (DHEA), respectively [11,12] .…”

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)

“…As androgens have been implicated in the development and progression of several diseases, most notably prostatic cancer, a promising alternative to treatment with antihormones and LHRH analogues might be the use of selective inhibitors of P450 17 [3,4] . Recently we have shown [3,5,6] that a dihydro-or tetrahydro-naphthalene is able to give -after linkage with an N-containing heterocycle such as imidazole, pyrazine, or pyridine -highly potent inhibitors of P450 17 (e.g., I, Chart 1 [6] ). While the heterocyclic N complexes the heme iron of P450 17, the rest of the molecule interacts with the apoprotein moiety.…”