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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Keyword

Blood-brain barrier (BBB)

brain drug delivery

neuropharmacokinetics

in silico modeling

PLS analysis

BBB drug transport

intracellular accumulation

binding and distribution in the brain

Pharmacokinetics and Drug Therapy

Farmakokinetik och läkemedelsterapi

Publication and Content Type

ref (subject category)

art (subject category)