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 blood–brain 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 (Kp,uu,brain), intracellular accumulation (Kp,uu,cell), and binding and distribution in
the brain (Vu,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.