2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties

Recently, 2-[(3-methoxyphenylethyl)phenoxy]-moiety has been selected for the design and synthesis of new small ABCB1 inhibitors. In the present paper, this moiety has been linked through a spacer of 2−5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii...

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Veröffentlicht in:Journal of medicinal chemistry 2008-12, Vol.51 (23), p.7602-7613
Hauptverfasser: Colabufo, Nicola Antonio, Berardi, Francesco, Perrone, Roberto, Rapposelli, Simona, Digiacomo, Maria, Vanni, Michael, Balsamo, Aldo
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Sprache:eng
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Zusammenfassung:Recently, 2-[(3-methoxyphenylethyl)phenoxy]-moiety has been selected for the design and synthesis of new small ABCB1 inhibitors. In the present paper, this moiety has been linked through a spacer of 2−5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii) N-4-methylpiperazine, and (iii) 6,7-dimethoxytetrahydroisoquinoline. The results demonstrated that all the selected basic nuclei were well tolerated and that, globally, the best inhibitory activity for each series was obtained when the spacer between the 2-[(3-methoxyphenylethyl)phenoxy] moiety and the basic nucleus consisted of a four-carbon chain. Among the synthesized compounds, N-4-methylpiperazine- 10c (IC50 = 0.15 μM) and tetrahydroisoquinoline-derivatives 11c (IC50 = 0.08 μM) with the spacer n = 4 for both series, displayed the best potency to inhibit ABCB1 activity. Moreover, for each compound, the ABCB1 interacting mechanism has been evaluated by three combined biological assays. N-4-methylpiperazine- (10a−d) and tetrahydroisoquinoline- (11a−d) derivatives were Cyclosporin A-like ABCB1 nontransported substrates.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800928j