1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: Syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase

A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphth alene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P 450 arom). Dual inhibition of these enzymes could be a novel strategy for t he 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-sa turated 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 referen ce compounds (dazoxiben: IC50 = 1.1 mu M; aminoglutethimide: IC50 = 18.5 mu M). For the determination of the in vivo activity, the influence of select ed compounds on serum TxB(2) concentration was examined in rats. Compound 3 0 (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 hi gh concentrations. Compound 30 inhibited P450 sec by 13% (25 mu M). Compoun d 31 did not affect cyclooxygenase and lipoxygenase.