Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates

In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the bloodbrain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (K-p,K-uu,K-brain), intracellular accumulation (K-p,K-uu,K-cell), and binding and distribution in the brain (V-u,V-brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties.