Abstract

In this study, lipophilicity of 21 cycloalkylspiro-5-hidantoins was assessed. The overall goal of lipophilicity evaluation is preliminary investigation which should result in a decrease of the traditionally high attrition rates for compounds entering clinical trials. Lipophilicity assessment was done by reversed-phase thin-layer chromatography and in silico methods. Chromatographic analyses were performed on C-18 modified thin-layer of silica gel with a two-component mobile phase consisting of water and organic solvent (acetonitrile, acetone, dioxane, or tetrahydrofuran) in different ratios. The chromatographic lipophilicities (R _M ⁰) were discussed and compared with computational log Ps calculated with various algorithms as well as in silico ADMET descriptors using linear regression and multivariate approach (hierarchical cluster analysis and principal component analysis). A high correlation was obtained between R _M ⁰ values and calculated log P indicating a strong relationship between the variables. Multivariate data analysis enabled the comparison of the chemical structures, lipophilicity, pharmacokinetic predictors and toxicity of the investigated compounds.

摘要

在这项研究中，评估了21个环烷基螺基5-hidantoins的亲脂性。亲脂性评估的总体目标是初步研究，这应导致进入临床试验的化合物的传统高磨损率降低。亲脂性评估是通过反相薄层色谱法和计算机方法进行的。色谱分析是在C-18改性硅胶薄层上进行的，两层流动相由不同比例的水和有机溶剂（乙腈，丙酮，二恶烷或四氢呋喃）组成。讨论了色谱亲油性（R _M ⁰），并与用各种算法计算的计算log P s和insilico ADMET描述符中使用线性回归和多元方法（层次聚类分析和主成分分析）。在R _M ⁰值和计算出的log P之间获得了高度相关性，表明变量之间存在强相关性。多元数据分析可以比较所研究化合物的化学结构，亲脂性，药代动力学预测因子和毒性。