Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates.
Mol Pharm
; 12(2): 520-32, 2015 Feb 02.
Article
in En
| MEDLINE
| ID: mdl-25496026
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Blood-Brain Barrier
/
Central Nervous System Agents
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Mol Pharm
Journal subject:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Year:
2015
Document type:
Article
Affiliation country:
Sweden