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Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates

(2015) MOLECULAR PHARMACEUTICS. 12(2). p.520-532
Author
Organization
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 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.
Keywords
brain drug delivery, neuropharmacokinetics, blood-brain barrier (BBB), in silico modeling, PLS analysis, BBB drug transport, intracellular accumulation, binding and distribution in the brain, IN-SILICO PREDICTION, PLASMA-CONCENTRATION RATIO, CENTRAL-NERVOUS-SYSTEM, P-GLYCOPROTEIN EFFLUX, BARRIER PERMEABILITY, TISSUE BINDING, PROTEIN, MODEL, DISCOVERY, DELIVERY

Citation

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MLA
Loryan, Irena, et al. “Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates.” MOLECULAR PHARMACEUTICS, vol. 12, no. 2, 2015, pp. 520–32, doi:10.1021/mp5005965.
APA
Loryan, I., Sinha, V., Mackie, C., Van Peer, A., Drinkenburg, W. H., Vermeulen, A., … Wassvik, C. M. (2015). Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates. MOLECULAR PHARMACEUTICS, 12(2), 520–532. https://doi.org/10.1021/mp5005965
Chicago author-date
Loryan, Irena, Vikash Sinha, Claire Mackie, Achiel Van Peer, Wilhelmus H Drinkenburg, An Vermeulen, Donald Heald, Margareta Hammarlund-Udenaes, and Carola M Wassvik. 2015. “Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates.” MOLECULAR PHARMACEUTICS 12 (2): 520–32. https://doi.org/10.1021/mp5005965.
Chicago author-date (all authors)
Loryan, Irena, Vikash Sinha, Claire Mackie, Achiel Van Peer, Wilhelmus H Drinkenburg, An Vermeulen, Donald Heald, Margareta Hammarlund-Udenaes, and Carola M Wassvik. 2015. “Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates.” MOLECULAR PHARMACEUTICS 12 (2): 520–532. doi:10.1021/mp5005965.
Vancouver
1.
Loryan I, Sinha V, Mackie C, Van Peer A, Drinkenburg WH, Vermeulen A, et al. Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates. MOLECULAR PHARMACEUTICS. 2015;12(2):520–32.
IEEE
[1]
I. Loryan et al., “Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates,” MOLECULAR PHARMACEUTICS, vol. 12, no. 2, pp. 520–532, 2015.
@article{7155731,
  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 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.}},
  author       = {{Loryan, Irena and Sinha, Vikash and Mackie, Claire and Van Peer, Achiel and Drinkenburg, Wilhelmus H and Vermeulen, An and Heald, Donald and Hammarlund-Udenaes, Margareta and Wassvik, Carola M}},
  issn         = {{1543-8384}},
  journal      = {{MOLECULAR PHARMACEUTICS}},
  keywords     = {{brain drug delivery,neuropharmacokinetics,blood-brain barrier (BBB),in silico modeling,PLS analysis,BBB drug transport,intracellular accumulation,binding and distribution in the brain,IN-SILICO PREDICTION,PLASMA-CONCENTRATION RATIO,CENTRAL-NERVOUS-SYSTEM,P-GLYCOPROTEIN EFFLUX,BARRIER PERMEABILITY,TISSUE BINDING,PROTEIN,MODEL,DISCOVERY,DELIVERY}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{520--532}},
  title        = {{Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates}},
  url          = {{http://doi.org/10.1021/mp5005965}},
  volume       = {{12}},
  year         = {{2015}},
}

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