Shamovsky Igor, de Graaf Chris, Alderin Lisa, Bengtsson Malena, Bladh Håkan, Börjesson Lena, Connolly Stephen, Dyke Hazel J, van den Heuvel Marco, Johansson Henrik, Josefsson Bo-Göran, Kristoffersson Anna, Linnanen Tero, Lisius Annea, Männikkö Roope, Nordén Bo, Price Steve, Ripa Lena, Rognan Didier, Rosendahl Alexander, Skrinjar Marco, Urbahns Klaus
Department of Medicinal Chemistry, AstraZeneca R&D Lund, S-22187 Lund, Sweden.
J Med Chem. 2009 Dec 10;52(23):7706-23. doi: 10.1021/jm900713y.
The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.
通过主成分分析研究了一系列CCR8拮抗剂与hERG离子通道和细胞色素Cyp2D6结合的代谢稳定性和选择性。结果表明，通过构建与CCR8的非去溶剂化相关吸引相互作用来降低化合物亲脂性，是提高该系列化合物代谢稳定性和选择性的有效方法，三维受体模型对此进行了合理说明。尽管这种极性相互作用导致化合物选择性增加，但这种策略也可能危及化合物的药物代谢动力学特征。然而，一旦发现活性增加，就可以通过构建适合CCR8但不适合hERG的疏水取代基来重新调整亲脂性。通过基于二维片段的QSAR分析鉴定了几个这样的亲脂性片段。电生理测量和定点诱变研究表明，这些片段与hERG的排斥相互作用是由与残基F656的空间位阻引起的。
