Hu Yiding, Sampson Kathleen E, Xing Li, Li Na, Heyde Bruce R, Xie Jin, Lai Yurong
Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
Drug Metab Lett. 2010 Dec;4(4):254-61. doi: 10.2174/187231210792928215.
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.
此前我们证明，形成三维构象的两个联苯环之间的扭转角是多药耐药蛋白2（Mrp2/Abcc2）相互作用的决定性因素[1]。最近，我们报道了一种杂环化合物，1-(1-(4-溴苯基)-3-氨基甲酰基-1H-吡唑-4-基)脲，它与联苯取代的杂环化合物具有相同的极性头部基团，可通过Mrp2/Abcc2从胆汁中大量分泌[2]。综合来看，我们推测两个分支极性基团和连接子可能是必不可少的，推测Mrp2/Abcc2识别适合于结合位点深处的两个主要正电区域。为了验证这一假设，我们检测了一种先导化合物（化合物1），以确认Mrp2/Abcc2参与导致大鼠肝胆分泌。我们进一步研究了一系列噻吩酰胺衍生物中Mrp2/Abcc2识别的结构要求，这些衍生物分为八个结构类别，结构变化集中在酰胺连接子的方向或从酰胺和磺酰胺到烯烃、烷烃或炔烃连接子的取代。在Caco-2细胞双向转运试验和Mrp2/Abcc2膜囊泡摄取试验中，在含有极性酰胺或磺酰胺连接子的结构类别1-5中证实了Mrp2/Abcc2介导的转运参与，但在具有非极性脂肪族连接子的类别6-8中未证实。在预测性贝叶斯模型中，Mrp2/Abcc2识别与结构描述符以及极性表面积和亲脂性（LogP）显示出强相关性。该结果为在计算机模拟中预测转运体识别提供了有价值的信息，有助于在早期药物发现中更好地预测涉及药物代谢动力学的转运体。
