1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: Syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase
C. Jacobs et al., 1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: Syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase, J MED CHEM, 43(9), 2000, pp. 1841-1851
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.