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.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Binding Sites / drug effects
  • Caco-2 Cells
  • Cell Membrane Permeability / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Fluoresceins / chemistry
  • Fluoresceins / metabolism
  • Humans
  • Molecular Structure
  • Phenyl Ethers / chemical synthesis
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacology*
  • Receptor, Serotonin, 5-HT1A / drug effects
  • Receptors, Dopamine D2 / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Fluoresceins
  • Phenyl Ethers
  • Receptors, Dopamine D2
  • Receptor, Serotonin, 5-HT1A
  • fluorexon