Reversed- and normal-phase liquid chromatography in quantitative structure retention-property relationships of newly synthesized seco-androstene derivatives

The rational preselection of drug candidates includes also correlation between physico-chemical properties (lipophilicity, as the key one) and pharmacokinetic properties, as well as pharmacodynamic activity. Lipophilicity can be determined alternatively by chromatographic methods. Chromatographic behavior of nineteen newly synthesized derivatives of 16-cyano-16,17-seco-5-androstene has been studied by reversed-phase and normal-phase thin-layer chromatography (RP- and NP-TLC). Commercial plates RP-C18-HPTLC and water-dioxane and water-acetonitrile, as well as Lux (R) silica gel plates and toluene-dioxane and toluene-acetonitrile mixtures with different volume fractions of the solvents were used. Retention constants R-M(0) and C-0 for each compound were determined and correlated with (i) theoretical log P values and (ii) pharmacokinetic predictors determined in silico. Significant linear relationship was found between RP TLC retention constants, R-M(0), and computational logP values as well as between NP TLC retention constants, C-0, and logP. Lipophilicity values for the analytes, determined by RP TLC and NP TLC, were also correlated with computer calculated absorption constants, affinity for plasma proteins, volume of distribution and logarithm of blood-brain permeation. Significant linear relationships were obtained. These relations were further improved by introducing other regressors, as molecular size descriptors (molecular mass and/or volume) and a molecular polarity descriptor (total polar surface area). Retention parameters, R-M(0) and C-0, are recommended for lipophilicity expression of analyzed compounds. In silico pharmacokinetic descriptors for the analytes can be expressed as function of the lipophilicity determined by chromatographic methods, the size and the polarity of the molecules expressed as molecular mass/volume and total polar surface area. The analyzed seco-androstene derivatives have adequate lipophilicity which should provide druglikeness and good pharmacokinetic profiles and they can be recommended for further studies in which their biological activity would be examined. (C) 2013 Elsevier B.V. All rights reserved.