1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase
| Autor: | Rolf Hartmann, Gerd Dannhardt, Christoph Jacobs, Martin Frotscher |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Thromboxane Stereochemistry In Vitro Techniques Substrate Specificity Rats Sprague-Dawley Thromboxane A2 chemistry.chemical_compound Lipoxygenase Microsomes Drug Discovery Animals Humans Dazoxiben Isoquinoline Enzyme Inhibitors biology Aromatase Inhibitors Imidazoles Rats Thromboxane B2 chemistry biology.protein Quinolines Molecular Medicine Spectrophotometry Ultraviolet Thromboxane-A synthase Cyclooxygenase Thromboxane-A Synthase |
| Zdroj: | Journal of medicinal chemistry. 43(9) |
| ISSN: | 0022-2623 |
| Popis: | 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): IC(50) = 0.29 microM; P450 arom: IC(50) = 0.50 microM) and its 5, 6-saturated analogue 30 (P450 TxA(2): IC(50) = 0.68 microM; P450 arom: IC(50) = 0.38 microM), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben: IC(50) = 1.1 microM; aminoglutethimide: IC(50) = 18.5 microM). 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 TxB(2) 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 scc by 13% (25 microM). Compound 31 did not affect cyclooxygenase and lipoxygenase. |
| Databáze: | OpenAIRE |
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