title: Two branched polar groups and polar linker moieties of thiophene amide derivatives are essential for MRP2/ABCC2 recognition.
abstract: Previously we demonstrated that the torsion angle between two biphenyl rings forming a three-dimensional conformation is the determinant factor for multi-drug resistance protein 2 (Mrp2/Abcc2) interaction [1]. More recently, we reported a heterocyclic compound, 1-(1-(4-bromophenyl)-3-carbamoyl-1H-pyrazol-4-yl) urea that shares the polar head groups with the biphenyl-substituted heterocycles, is highly secreted from bile by Mrp2/Abcc2, [2]. Collectively we hypothesized that the two branched polar groups and linkers might be essential with proposed Mrp2/Abcc2 recognition fitting in two primarily positive regions deep in the binding site. To test the hypothesis, a discovery lead compound (Compound 1) was examined to confirm the Mrp2/Abcc2 involvement resulting in hepatobiliary secretion in rats. The structural requirement of Mrp2/Abcc2 recognition was further explored in a series of thiophene amides derivatives divided into eight structural classes, with structural changes focused on the amide linker orientation or substitution from amide and sulfonamide to alkene, alkane, or alkyne linkers. In Caco-2 cell bidirectional transport assays and Mrp2/Abcc2 membrane vesicle uptake assays, the involvement of Mrp2/Abcc2 mediated transport was confirmed in structural classes 1 - 5, which contains polar amide or sulfonamide linker, but not in classes 6 - 8 with non-polar aliphatic linker. The Mrp2/Abcc2 recognition showed strong correlation with structural descriptors in predictive Bayesian model, as well as with polar surface area and lipophilicity (LogP). The result provided valuable information for predicting transporter recognition in silico, for improved predictions of transporter involved ADME in early drug discovery.
authors.affiliation: Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Yiding
authors.initials: Y
authors.lastname: Hu
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sampson
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Heyde
authors.forename: Jin
authors.initials: J
authors.lastname: Xie
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001499:Bayes Theorem; D001646:Bile / Q000378:metabolism; D001692:Biological Transport; D018938:Caco-2 Cells; D004285:Dogs; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013876:Thiophenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014162:Transfection
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D013876:Thiophenes; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C423013:Abcc2 protein, rat