N-imidazolyl derivatives of the napththalene and chroman rings as thromboxane A2 synthase inhibitors

Cozzi, Paolo; Branzoli, Umberto; Carganico, G.; Ferti, C.; Pillan, Antonio; Severino, D.; Tonani, R.

doi:10.1016/0223-5234(91)90103-t

Cited by 13 publications

(7 citation statements)

References 51 publications

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“…Inhibition of P450 TXA 2 . It has been known for some time that 1-imidazolyl-substituted tetrahydronaphthalenes are strong inhibitors of thromboxane A 2 (TXA 2 ) synthase, depending on the substituent at the benzene nucleus . Since inhibition of this enzyme, which contains a P450 moiety, might influence haemostatic function, select compounds were tested for inhibition of TXA 2 synthase (Table ).…”

Section: Biological Propertiesmentioning

confidence: 99%

Tetrahydronaphthalenes: Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

et al. 1996

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In search of new leads for selective inhibition of estrogen and androgen biosynthesis, respectively, heterocyclic substituted 2-(arylmethylene)-1-tetralones (1-4, 9-17), 2-(aryl-hydroxymethyl)-1-tetralones (5-8), exo-1a,2,3,7b-tetrahydro-1H-cyclopropa[alpha] naphthalenes (18-24), and 3-alkyl substituted 4,5-dihydronaphtho[1,2-c]pyrazoles (25-27) were synthesized and tested for inhibitory activity toward four steroidogenic enzymes (P450 arom, P450 17, P450 18, and P450 scc, as well as another P450 enzyme, thromboxane A(2) (TXA(2)) synthase. The test compounds inhibited human placental P450 arom, showing a wide range of inhibitory potencies. (Z)-4-Imidazolyl compound 17 was the most potent inhibitor, with a relative potency (rp) of 110 [rp of aminoglutethimide (AG) = 1), rp of fadrozole = 359]. A competitive type of inhibition was shown by the (E)-4-imidazolyl compound 16(rp = 71). On the other hand some of these compounds inhibited rat testicular P450 17. Maximum activity was shown by the 3-pyridyl compound 20 (rp = 10, ro of ketoconazole = 1). 20 was the only compound which exhibited a marked inhibition of TXA(2) synthase (IC(50) = 14.5 microM; IC(50) of dazoxiben = 1.1 microM). Regarding selectivity toward the steroidogenic enzymes, compound 16 was relatively selective toward P450 arom, whereas compound 20 was relatively selective toward P450 17. (P450 arom: K(m) testosterone = 42 nM, K(i)16 = 33 nM, K(i)20 = 3 microM. P450 17: K(m)progesterone = 7 microM, K(i)16 = 9 microM, K(i)20 = 80 nM). 17 and 24 were not selective since they showed strong inhibition of P450 arom (K(i)17 = 26 nM, K(i)24 = 0.12 microM) and P450 17 (K(i) 17 = 0.7 microM, K(i)24 = 0.11 microM).

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Section: Biological Propertiesmentioning

confidence: 99%

Tetrahydronaphthalenes: Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

et al. 1996

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“…45 Alternatively, examples of natural (E)-dehydrohistidine are few, and roquefortine is an exception that has been of interest due to its antibacterial activities. 10 The first total synthesis of roquefortine was recently reported using a novel elimination strategy. 46 In the urocanic acid series, cis isomers exhibit higher inhibition strength towards P450s and MP8.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4][5] Their inhibitory potency comes from their ability to form stable Fe(II)-N-imidazole complexes. 6 Numerous imidazole derivatives were investigated for their ability to inhibit hemoproteins such as cytochromes P450, 2,4-9 cyclo-oxygenases 10 and NO-synthases. 11 They are also known and used for their potent inhibition of lanosterol demethylase activity in fungi.…”

Section: Introductionmentioning

confidence: 99%

Intramolecular hydrogen bonding as a determinant of the inhibitory potency of N-unsubstituted imidazole derivatives towards mammalian hemoproteins

et al. 2009

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Enzymes involved in the mammalian microsomal metabolism of drugs are, in numerous cases, inhibited by compounds bearing an imidazolyl scaffold. However, the inhibition potency is highly dependent upon the accessibility of the imidazolyl nitrogen lone pair. In order to highlight some structural parameters of inhibitors that control this phenomenon, a series of compounds containing a nitrogen unsubstituted imidazolyl moiety with varying degrees of nitrogen lone pair accessibility was tested on human and rat hepatic cytochromes P450 and microperoxidase 8, an enzymatically active peptide derived from cytochrome c. In each case, we have shown that the accessibility of the imidazole lone pair determined the extent of inhibition. Nitrogen accessibility was tuned not only by varying the steric hindrance in the vicinity of the imidazolyl ring but also by modifying its surrounding hydrogen bonding network. Compounds in which there exists intramolecular hydrogen bonding between the imidazole moiety and an H-bond acceptor, such as an appropriately positioned amide carbonyl group, demonstrated enhanced inhibitory effects. Conversely, imidazole moieties which are in proximity to H-bond donors, such as an amide NH group, displayed reduced potency. This trend was observed in cyclo-peptide derivatives in which the intramolecular H-bond network was adjusted through the modification of the stereochemistry of a dehydrohistidine residue. It was observed that (Z)-isomers weakly bind heme, whereas (E)-isomers demonstrated higher degrees of metal binding. Therefore, enzymatic inhibition of heme-containing proteins by compounds bearing a dehydrohistidine motif seems to be closely related to its stereochemistry and hydrogen binding propensity. At neutral pH, these differences in binding affinities can be confidently attributed to the ambident H-bond properties of imidazole nitrogen atoms. This structure-activity relationship may be of use for the design of novel imidazolyl compounds as new P450 inhibitors or drug candidates.

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“…For the assessment of the in vivo inhibition, P450 TxA 2 was chosen rather than P450 arom 31 because the former assay is easier to perform. After stability at pH 7.4 and 2.0 had been demonstrated (no degradation observed after 24 h), homologous compounds 29 − 31 were applied to rats and the serum TxB 2 levels were determined after 2, 3, 5, and 8 h by radioimmunoassay (Table ). The test compounds and dazoxiben show a strong reduction of the TxB 2 concentration after 2 h. In the case of compound 31 , which is the most active inhibitor in vitro, no inhibition was observed after 5 h indicating that the Δ5 double bond diminishes in vivo activity.…”

Section: Biological Propertiesmentioning

confidence: 99%

1-Imidazolyl(alkyl)-Substituted Di- and Tetrahydroquinolines and Analogues: Syntheses and Evaluation of Dual Inhibitors of Thromboxane A₂ Synthase and Aromatase

et al. 2000

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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.

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N-imidazolyl derivatives of the napththalene and chroman rings as thromboxane A2 synthase inhibitors

Cited by 13 publications

References 51 publications

Tetrahydronaphthalenes: Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

Tetrahydronaphthalenes: Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

Intramolecular hydrogen bonding as a determinant of the inhibitory potency of N-unsubstituted imidazole derivatives towards mammalian hemoproteins

1-Imidazolyl(alkyl)-Substituted Di- and Tetrahydroquinolines and Analogues: Syntheses and Evaluation of Dual Inhibitors of Thromboxane A₂ Synthase and Aromatase

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N-imidazolyl derivatives of the napththalene and chroman rings as thromboxane A2 synthase inhibitors

Cited by 13 publications

References 51 publications

Tetrahydronaphthalenes: Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

Tetrahydronaphthalenes: Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

Intramolecular hydrogen bonding as a determinant of the inhibitory potency of N-unsubstituted imidazole derivatives towards mammalian hemoproteins

1-Imidazolyl(alkyl)-Substituted Di- and Tetrahydroquinolines and Analogues: Syntheses and Evaluation of Dual Inhibitors of Thromboxane A2 Synthase and Aromatase

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1-Imidazolyl(alkyl)-Substituted Di- and Tetrahydroquinolines and Analogues: Syntheses and Evaluation of Dual Inhibitors of Thromboxane A₂ Synthase and Aromatase