1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues:: Syntheses and evaluation of dual inhibitors of thromboxane A2 synthase and aromatase

A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA(2): IC50 = 0.29 mu M; P450 arom: IC50 = 0.50 mu M) and its 5,6-saturated analogue 30 (P450 TxA(2): IC50 = 0.68 mu M; P450 arom: IC50 = 0.38 mu M), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben: IC50 = 1.1 mu M; aminoglutethimide: IC50 = 18.5 mu M). For the determination of the in vivo activity, the influence of selected compounds on serum TxB(2) concentration was examined in rats. Compound 30 (8.5 mg/kg body weight) led to a reduction of the TxB2 serum level of 78%, 71%, and 51% after 3, 5, and 8 h, respectively (dazoxiben: 60%, 34%, and 36%). Selectivity was studied toward some enzymes of the steroidogenic and eicosanoid pathways. P450 17 was inhibited by selected compounds only at high concentrations. Compound 30 inhibited P450 sec by 13% (25 mu M). Compound 31 did not affect cyclooxygenase and lipoxygenase.