Tuning properties for blood-brain barrier permeation: a statistics-based analysis

In the effort to define a set of rules useful in tuning the properties for a successful blood-brain barrier (BBB) permeation, we statistically analyzed a set of 328 compounds and correlated their experimental in vivo logBB with a series of computed descriptors. Contingency tables were constructed, observed and expected distributions were calculated, and chi-square (χ2) distributions were evaluated. This allowed to point out a significant dependence of certain physicochemical properties in influencing the BBB permeation. Of over 15 computed descriptors, 9 resulted to be particularly important showing highly significant χ2 distribution: Polar surface area (χ2 = 66.79; p = 1.08 × 10-13), nitrogen and oxygen count (χ2 = 51.17; p = 2.06 × 10-10), logP (χ2 = 47.38; p = 1.27 × 10-9), nitrogen count (χ2 = 38.29; p = 9.77 × 10-8), logD (χ2 = 36.80; p = 36.80), oxygen count (χ2 = 35.83; p = 3.13 × 10-7), ionization state (χ2 = 33.02, p = 3.19 × 10-7), hydrogen bond acceptors (χ2 = 30.80; p = 3.36 × 10-6), and hydrogen bond donors (χ2 = 29.29; p = 6.81 × 10-6). Other parameters describing the mass and size of the molecules (molecular weight: 11.18; p = 2.46 × 10-2) resulted in being not significant since the population within the observed and expected distribution was similar. Depending on the combination of the significant descriptors, we set a three cases probabilistic scenario (BBB+, BBB-, BBB+/BBB-) that would prospectively be used to tune properties for BBB permeation.