2-[(3-Methoxyphenylethyl)phenoxy]-based ABCB1 inhibitors: effect of different basic side-chains on their biological properties.

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Colabufo NA, Berardi F, Perrone R, Rapposelli S, Digiacomo M, Vanni M, Balsamo A

2-[(3-Methoxyphenylethyl)phenoxy]-based ABCB1 inhibitors: effect of different basic side-chains on their biological properties.

J Med Chem. 2008 Dec 11;51(23):7602-13. doi: 10.1021/jm800928j.

PubMed ID

19053888 [ View in PubMed

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Abstract

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 (IC(50) = 0.15 microM) and tetrahydroisoquinoline-derivatives 11c (IC(50) = 0.08 microM) 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Elacridar	P-glycoprotein 1	IC 50 (nM)	2000	N/A	N/A	Details
Haloperidol	Dopamine D2 receptor	Ki (nM)	6400	N/A	N/A	Details