Aromatic 2-(thio)ureidocarboxylic acids as a new family of modulators of multidrug resistance-associated protein 1: synthesis, biological evaluation, and structure-activity relationships.

Full Abstract

Four series of aromatic carboxylic acids were prepared with a urea or thiourea moiety at the neighboring position to the carboxyl group and benzene or thiophene as aromatic scaffold. Using a calcein AM assay, these compounds were evaluated as inhibitors of multidrug resistance-associated protein 1 (MRP1) and selected compounds were examined toward P-glycoprotein (P-gp) as well as breast cancer resistance protein (BCRP) to assess selectivity for MRP1. Two 2-thioureidobenzo[b]thiophene-3-carboxylic acids (48, 49) were identified as particularly potent inhibitors of MRP1, with IC50 values of around 1 microM. The structural features of this new family of nontoxic MRP1 inhibitors include a (thio)urea disubstituted with preferentially two alkyl groups at the terminal nitrogen and an additional fused aromatic ring.

Author information

Author/s: Häcker, Hans-Georg (HG); Leyers, Stefan (S); Wiendlocha, Jeanette (J); Gütschow, Michael (M); Wiese, Michael (M);

Affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of medicinal chemistry (J Med Chem), published in United States. (Language: eng)

Reference: 2009-Aug; vol 52 (issue 15) : pp 4586-95

Dates: Created 2009/09/01; Completed 2009/09/21;

PMID: 19580319, status: MEDLINE (last retrieved date: 9/21/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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Associated Chemicals: ABCG2 protein, human (0) ; ATP-Binding Cassette Transporters (0) ; Carboxylic Acids (0) ; Multidrug Resistance-Associated Proteins (0) ; Neoplasm Proteins (0) ; P-Glycoprotein (0) ; multidrug resistance-associated protein 1 (0)

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