title: A 4-aminobenzoic acid derivative as novel lead for selective inhibitors of multidrug resistance-associated proteins.
abstract: We present a novel lead for inhibitors of multidrug resistance-associated proteins (MRPs). Compound 1 (4-[(5,6,7,8-tetrahydro-4-oxo-4H-[1]benzothieno[2,3-d][1,3]thiazin-2-yl)amino]benzoic acid) was about six times more potent than the known inhibitor MK571 at MRP1, while at MRP2 its effect was similar to that of MK571. Structural analogs were also evaluated. Among them, compound 2, sharing the 4-aminobenzoic acid substructure with 1, also inhibited MRP1. Both derivatives were inactive against P-gp. It can be concluded that their carboxyl group is needed for inhibition of MRPs and accounts for the selectivity of these compounds.
authors: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors: Stefan
authors: S
authors: Leyers
authors: Hans-Georg
authors: HG
authors: Häcker
authors: Jeanette
authors: J
authors: Wiendlocha
authors: Michael
authors: M
authors: Gütschow
authors: Michael
authors: M
authors: Wiese
mesh_terms: D010129:4-Aminobenzoic Acid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology*; D062366:para-Aminobenzoates
chemical_list: D010129:4-Aminobenzoic Acid; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013843:Thiazines; D062366:para-Aminobenzoates; C532452:4-((5,6,7,8-tetrahydro-4-oxo-4H-(1)benzothieno(2,3-d)(1,3)thiazin-2-yl)amino)benzoic acid; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1