Ionization-specific QSAR models of blood-brain penetration of drugs.

This study presents a mechanistic QSAR (quantitative structure-activity relationship) analysis of blood-brain barrier (BBB) penetration of drugs and drug-like compounds governed by passive diffusion in rats and mice. The analyzed data included a previously compiled set of almost 200 experimental BBB permeation rates (expressed as log PS values) as well as steady-state brain/plasma distribution ratios for ca. 500 compounds (represented as log BB constants) that were considered free of carrier-mediated transport and other unwanted effects. These data were modeled in terms of nonlinear lipophilicity and ionization dependences. The necessity to separate the influence of drug binding to plasma and brain constituents on the distribution ratio is discussed. Preliminary results demonstrate that, if both the rate and extent of BBB penetration are considered, it is possible to estimate whether a given compound may exhibit central nervous system (CNS) penetration.