title: A structure-activity relationship study of ABCC2 inhibitors.
abstract: Multidrug resistance associated protein 2 (MRP2/ABCC2) is a membrane transport protein that can potentially affect the disposition of many substrate drugs and their metabolites. Recently, we studied the interaction of a library of 432 compounds with ABCC2, and the structure-activity relationship (SAR) of a subset of 64 compounds divided into four scaffolds (Wissel, G. et al., 2015. Bioorg Med Chem., 23(13), pp.3513-25). We have now expanded this test set by investigating 114 new compounds, of which 71 are representative of the previous four scaffolds and 43 compounds belong to a new scaffold. Interaction with ABCC2 was assessed by measuring the compounds effect on 5(6)-carboxy-2',7'-dichlorofluorescein transport in the vesicular transport assay. In line with our previous study, we observed that anionic charge is not essential for inhibition of ABCC2 transport, even though it often increases the inhibitory activity within the analogue series. Additionally, we found that halogen substitutions often increase the inhibitory activity. The results confirm the importance of structural features such as aromaticity and lipophilicity for ABCC2 inhibitory activity.
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Gloria
authors.initials: G
authors.lastname: Wissel
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Feng
authors.initials: F
authors.lastname: Deng
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kudryavtsev
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Leo
authors.initials: L
authors.lastname: Ghemtio
authors.affiliation: Department of Chemistry, The Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Henri
authors.initials: H
authors.lastname: Xhaard
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Electronic address: heidi.kidron@helsinki.fi.
authors.forename: Heidi
authors.initials: H
authors.lastname: Kidron
mesh_terms: D001692:Biological Transport; D005452:Fluoresceins / Q000737:chemistry; D008958:Models, Molecular; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D005452:Fluoresceins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C053897:5(6)-carboxy-2',7'-dichlorofluorescein
keywords: MRP2; Modulator; Pharmacophore; Transporter; Vesicle assay