The DOI matches its Crossref record; 135 of the 135 references it cites were found in a registry or an index.
Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective
Abstract
In the development of central nervous system (CNS) drugs, the blood-brain barrier (BBB) restricts many drugs from entering the brain to exert therapeutic effects. Although many novel delivery methods of large molecule drugs have been designed to assist transport, small molecule drugs account for the vast majority of the CNS drugs used clinically. From this perspective, we review studies from the past five years that have sought to modify small molecules to increase brain exposure. Medicinal chemists make it easier for small molecules to cross the BBB by improving diffusion, reducing efflux, and activating carrier transporters. On the basis of their excellent work, we summarize strategies for structural modification of small molecules to improve BBB penetration. These strategies are expected to provide a reference for the future development of small molecule CNS drugs.
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“However, the delivery of mRNA to the brain remains a formidable challenge due to the blood–brain barrier (BBB)18,19.”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [18]
Citations
Cites
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(96)00423-1 · Cited by 11,484
Feigin, V. L., Nichols, E., Alam, T., Bannick, M. S., Beghi, E., Blake, N., Culpepper, W. J., Dorsey, E. R., Elbaz, A., Ellenbogen, R. G., et al. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30499-x · Cited by 5,644
Drug-like properties and the causes of poor solubility and poor permeability
Lipinski, C. A. (2000) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/s1056-8719(00)00107-6 · Cited by 3,776
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.09.019 · Cited by 3,720
Applications of Fluorine in Medicinal Chemistry
Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J., & Meanwell, N. A. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00258 · Cited by 3,692
Ertl, P., Rohde, B., & Selzer, P. M. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm000942e · Cited by 3,149
2019 Alzheimer’s disease facts and figures.
Alzheimer's Association (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.01.010 · Cited by 2,461
The blood–brain barrier and blood–tumour barrier in brain tumours and metastases
Arvanitis, C., Ferraro, G. B., & Jain, R. K. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0205-x · Cited by 1,919
Medicinal chemical properties of successful central nervous system drugs
Pajouhesh, H., & Lenz, G. R. (2005) · NeuroRx · doi:10.1602/neurorx.2.4.541 · Cited by 1,608
Kansy, M., Senner, F., & Gubernator, K. (1998) · Journal of Medicinal Chemistry · doi:10.1021/jm970530e · Cited by 1,304
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Okafor, N. I., Abdelgader, A., Abobaker, M., & Choonara, Y. E. (2026) · ChemistryOpen · doi:10.1002/open.202500425
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Rachana, S. P., Pokale, R., Datta, D., Naik, G. A. R. R., Jadhav, S. R., Kudarha, R. R., Mutalik, S., & Dhas, N. L. (2026) · AAPS PharmSciTech · doi:10.1208/s12249-026-03522-3
Hu, Y., Zhang, C., Zhang, Z., Wu, H., Chong, W., Dong, Z., Shang, L., & Li, L. (2026) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.6c00341
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Chen, H., Li, X., Liu, S., Li, Z., Liu, W., Ye, X., Zheng, F., Zeng, X., Lin, J., Yang, A., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c01681
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Simić, S., Leuci, R., Pirker, M., Kalaba, P., Wackerlig, J., Piemontese, L., & Langer, T. (2026) · ACS Omega · doi:10.1021/acsomega.6c07555
Xiong, B., Zhen, T., Wang, X., Zhang, W., Zhiqiang, W., Ma, M., Bai, X., Zhu, J., Zheng, N., Wei, Y., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c02238
Self-citationAzuaje, J., Prieto‐Díaz, R., Gioé-Gallo, C., Ortigueira, S., Soilán, J., Triñanes, D., Fojo, H., Loza, M. I., Contino, M., Perrone, M. G., et al. (2026) · ACS Omega · doi:10.1021/acsomega.6c07565
Feng, Z., Fan, Y., Du, T., Huang, P., Ye, Y., & Li, J. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.71208
Yao, B., Mao, W., 王明华, Zhang, J., Xie, S., Cheng, K., Hu, X., Liu, W., Zhang, X., Zhengqing, Z., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c02121
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Shi, D., Luo, Y., Zhou, H., Schmidt, O. G., Li, J., & Zhang, J. (2026) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2026.218691
del Río, N., Rodríguez-Tacón, A., Escribano-Romero, E., Álvarez-Mínguez, A., Gargantilla, M., Caridi, F., Poderoso, T., Quesada, E., Kauerová, T., Kollár, P., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c01236
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BindingDB (2023) · UC San Diego · doi:10.7270/q2j10735
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Ali, S. B., Jamal, M., Ayub, M., Nisar, U., Malhi, S. M., Faizi, S., Sımjee, S. U., & Iriti, M. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.111244
Metadata
- Authors
- Xiong, B., Wang, Y., Chen, Y., Xing, S., Liao, Q., Chen, Y., Li, Q., Li, W., & Sun, H.
- Affiliations
- China Pharmaceutical University (CN)
- Nanjing University of Chinese Medicine (CN)
- Qingdao University (CN)
- Corresponding author
- Li, Qi
- Li, Wei
- Sun, Haopeng
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-09-10
- Volume
- 64
- Issue
- 18
- Pages
- 13152-13173
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W3196964953
- Cited by
- 232
- References
- 135
- Citations by year
- 2026: 49 · 2025: 66 · 2024: 58 · 2023: 44 · 2022: 13 · 2021: 2
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- China Pharmaceutical University (CPU2018GF11, CPU2018GY34)
- Natural Science Foundation of Jiangsu Province (BK20191411)
- National Natural Science Foundation of China (81573281, 81872728, 81973207)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- blood-brain barrier, blood-brain barrier penetration, structural modification, brain drug delivery, passive diffusion, efflux pumps, carrier-mediated transport, CNS drug development
- MeSH terms
- Animals, Blood-Brain Barrier, Central Nervous System Agents, Humans, Hydrogen Bonding, Permeability, Molecular Structure, Transcytosis, Hydrophobic and Hydrophilic Interactions
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