Di Tullio Maurizio, Maccallini Cristina, Ammazzalorso Alessandra, Giampietro Letizia, Amoroso Rosa, De Filippis Barbara, Fantacuzzi Marialuigia, Wiczling Paweł, Kaliszan Roman
Department of Drug Sciences, University 'G. d'Annunzio', Chieti, Italy.
Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gdańsk, Poland phone/fax: +48 58 349 32 60.
Mol Inform. 2012 Jul;31(6-7):453-8. doi: 10.1002/minf.201200001. Epub 2012 Jun 27.
A series of 27 analogues of clofibric acid, mostly heteroarylalkanoic derivatives, have been analyzed by a novel high-throughput reversed-phase HPLC method employing combined gradient of eluent's pH and organic modifier content. The such determined hydrophobicity (lipophilicity) parameters, log kw , and acidity constants, pKa , were subjected to multiple regression analysis to get a QSRR (Quantitative StructureRetention Relationships) and a QSPR (Quantitative Structure-Property Relationships) equation, respectively, describing these pharmacokinetics-determining physicochemical parameters in terms of the calculation chemistry derived structural descriptors. The previously determined in vitro log EC50 values - transactivation activity towards PPARα (human Peroxisome Proliferator-Activated Receptor α) - have also been described in a QSAR (Quantitative StructureActivity Relationships) equation in terms of the 3-D-MoRSE descriptors (3D-Molecule Representation of Structures based on Electron diffraction descriptors). The QSAR model derived can serve for an a priori prediction of bioactivity in vitro of any designed analogue, whereas the QSRR and the QSPR models can be used to evaluate lipophilicity and acidity, respectively, of the compounds, and hence to rational guide selection of structures of proper pharmacokinetics.
采用洗脱液pH值和有机改性剂含量的组合梯度，通过一种新型高通量反相HPLC方法分析了一系列27种氯贝酸类似物，其中大部分为杂芳基链烷酸衍生物。将如此测定的疏水性（亲脂性）参数log kw和酸度常数pKa进行多元回归分析，分别得到一个定量结构-保留关系（QSRR）方程和一个定量结构-性质关系（QSPR）方程，用计算化学推导的结构描述符来描述这些决定药代动力学的物理化学参数。先前测定的体外log EC50值——对PPARα（人过氧化物酶体增殖物激活受体α）的反式激活活性——也已根据3-D-MoRSE描述符（基于电子衍射描述符的结构的3D分子表示）在一个定量构效关系（QSAR）方程中进行了描述。所推导的QSAR模型可用于对任何设计的类似物的体外生物活性进行先验预测，而QSRR和QSPR模型可分别用于评估化合物的亲脂性和酸度，从而合理指导具有适当药代动力学的结构的选择。
