CNS Drug Design Based on Principles of Blood‐Brain Barrier Transport
Abstract
Abstract: Lipid‐soluble small molecules with a molecular mass under a 400–600‐Da threshold are transported readily through the blood‐brain barrier in vivo owing to lipid‐mediated transport. However, other small molecules lacking these particular molecular properties, antisense drugs, and peptide‐based pharmaceuticals generally undergo negligible transport through the blood‐brain barrier in pharmacologically significant amounts. Therefore, if present day CNS drug discovery programs are to avoid termination caused by negligible blood‐brain barrier transport, it is important to merge CNS drug discovery and CNS drug delivery as early as possible in the overall CNS drug development process. Strategies for special formulation that enable drug transport through the blood‐brain barrier arise from knowledge of the molecular and cellular biology of blood‐brain barrier transport processes.
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Passive transcytosis across the blood-brain barrier permits only hydrophilic compounds with a mass lower than 150 Da and highly hydrophobic compounds with a mass lower than 400-600 Da.
“The tightness of the BBB precludes the entrance of most pharmaceuticals into the brain via passive transcytosis, except for hydrophilic compounds which have a mass lower than 150 Da and highly hydrophobic compounds which have a mass lower than 400–600 Da.157,158”
From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [158]
Cites
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“Thereare occasionalexceptionsto themolecular weightthresholdrule suchas illustratedby 36- 733, whichhas amolecularmass of 590Da(Pardridge et al., 1990b), and 2 ‘,7 ‘-bis(2-carboxyethyl)-5(6)carboxyfluorescein acetoxymethylester (BCECFAM), whichhas amolecularmassof 809 Da (Hirohashi et al.,1997).”
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The blood–brain barrier: Structure, regulation and drug delivery
Wu, D., Chen, Q., Chen, X., Han, F., Chen, Z., & Wang, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01481-w · Cited by 1,906 · see citing works
“157,158 For this reason, if passive transcytosis is demanded to realize the delivery of the drugs at higher molecular weight, some strategies to enhance the BBB permeability or break BBB temporarily will be desired.”
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Essential Medicinal Chemistry of Essential Medicines
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- Authors
- Pardridge, W. M.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Pardridge, William M.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1998-05
- Volume
- 70
- Issue
- 5
- Pages
- 1781-1792
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1974129665
- Cited by
- 460
- References
- 1
- Citations by year
- 2026: 6 · 2025: 22 · 2024: 11 · 2023: 17 · 2022: 16 · 2021: 25 · 2020: 24 · 2019: 7 · 2018: 12 · 2017: 14 · 2016: 20 · 2015: 14 · 2014: 11 · 2013: 21 · 2012: 18
- FWCI
- 13.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS 34698, R01NS034698)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- blood-brain barrier, brain drug delivery, antisense therapeutics, peptide therapeutics, drug formulation
- MeSH terms
- Animals, Biological Transport, Blood-Brain Barrier, Brain, Humans, Molecular Weight, Pharmacokinetics, Drug Design, Antisense Elements (Genetics), Drug Delivery Systems
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