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Title: 2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2
Authors: Baiceanu, E
Nguyen, KA
Gonzalez-Lobato, L
Nasr, R
Baubichon-Cortay, H
Loghin, F
Le, Borgne, M
Chow, L 
Boumendjel, A
Peuchmaur, M
Falson, P
Keywords: ABC transporters
ABCC2 inhibitors
Drug interactions
Issue Date: 2016
Publisher: Elsevier Masson
Source: European journal of medicinal chemistry, 2016, v. 122, p. 408-418 How to cite?
Journal: European journal of medicinal chemistry 
Abstract: ABC-transporters play a vital role in drugs bioavailability. They prevent intracellular accumulation of toxic compounds, rendering them a major defense mechanism against harmful substances. In this large family, ABCC2 is an apical efflux pump representing about 10% of all membrane proteins in liver and small intestine, and up to 25% in colon. In these tissues, ABCC2 plays a major role in the pharmacokinetics and pharmacodynamics of endo- and xenobiotics. To gain insight in the function of this crucial protein, we have investigated and developed the first effective inhibitors of this pump. Firstly, we set up a cellular flow cytometry assay for monitoring the drug efflux carried out by ABCC2, and used it for the screening of chemical libraries derived from several chemical classes. We found that 2-indolylmethylenebenzofuranone derivatives as promising candidates. Optimization of the hits provided new compounds that inhibit ABCC2 in the micromolar range, making them the first potent ABCC2 inhibitors reported so far. Such compounds would constitute valuable tools to further investigate the role of ABCC2 in the pharmacokinetics and pharmacodynamics of drugs.
ISSN: 0223-5234
EISSN: 1768-3254
DOI: 10.1016/j.ejmech.2016.06.039
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