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Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Translational PKPD)ORCID iD: 0000-0002-1557-4416
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2015 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, 520-532 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
ACS Publications, 2015. 520-532 p.
Keyword [en]
Blood-brain barrier (BBB), brain drug delivery, neuropharmacokinetics, in silico modeling, PLS analysis, BBB drug transport, intracellular accumulation, binding and distribution in the brain
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
URN: urn:nbn:se:uu:diva-238894DOI: 10.1021/mp5005965ISI: 000348886900024PubMedID: 25496026OAI: oai:DiVA.org:uu-238894DiVA: diva2:772706
Available from: 2014-12-17 Created: 2014-12-17 Last updated: 2016-04-29

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Loryan, IrenaMargareta, Hammarlund-Udenaes
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Department of Pharmaceutical BiosciencesScience for Life Laboratory, SciLifeLabDivision of Pharmacokinetics and Drug Therapy
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Molecular Pharmaceutics
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