Cited by 236Barrier Structure and Function StudiesDrug Transport and Resistance MechanismsComputational Drug Discovery Methods

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

Xiong, Baichen, Wang, Yuanyuan, Chen, Ying, Xing, Shuaishuai, Liao, Qinghong, Chen, Yao, Li, Qi, Li, Wei, Sun, Haopeng·2021·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.1c00910

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1021/acs.jmedchem.1c00910

Cites

135 of 135 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
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
Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016
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
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
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
Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties
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
Physicochemical High Throughput Screening: Parallel Artificial Membrane Permeation Assay in the Description of Passive Absorption Processes
Kansy, M., Senner, F., & Gubernator, K. (1998) · Journal of Medicinal Chemistry · doi:10.1021/jm970530e · Cited by 1,304

Show all 135 references

Sorted by citations

Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system
Wang, C., Xue, Y., Markovic, T., Li, H., Wang, S., Zhong, Y., Du, S., Zhang, Y., Hou, X., Yu, Y., et al. (2025) · Nature Materials · doi:10.1038/s41563-024-02114-5 · Cited by 171
“However, the delivery of mRNA to the brain remains a formidable challenge due to the blood–brain barrier (BBB) 18,19 .”
Explaining Blood–Brain Barrier Permeability of Small Molecules by Integrated Analysis of Different Transport Mechanisms
Cornelissen, F. M. G., Markert, G., Deutsch, G., Antonara, M., Faaij, N., Bartelink, I. H., Noske, D. P., Vandertop, W. P., Bender, A., & Westerman, B. A. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01824 · Cited by 156
Extracellular Vesicles: A Review of Their Therapeutic Potentials, Sources, Biodistribution, and Administration Routes
Su, X., Wang, H., Li, Q., & Chen, Z. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s502591 · Cited by 126
Self-citation
NLRP3 Inflammasome-Mediated Neuroinflammation and Related Mitochondrial Impairment in Parkinson’s Disease
Han, Q.-Q., & Le, W. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01023-y · Cited by 106
Differential Signaling Pathways in Medulloblastoma: Nano-biomedicine Targeting Non-coding Epigenetics to Improve Current and Future Therapeutics
Sokolov, D., Sharda, N., Banerjee, A., Denisenko, K., Basalious, E. B., Shukla, H. D., Waddell, J., Hamdy, N. Μ., & Banerjee, A. (2023) · Current Pharmaceutical Design · doi:10.2174/0113816128277350231219062154 · Cited by 72
Current Chemical, Biological, and Physiological Views in the Development of Successful Brain-Targeted Pharmaceutics
Markowicz-Piasecka, M., Markiewicz, A., Darłak, P., Sikora, J., Adla, S. K., Bagina, S., & Huttunen, K. M. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01228-5 · Cited by 68
Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression
Han, Q.-Q., Li, W., Chen, P., Wang, L., Bao, X., Huang, R., Liu, G., & Chen, X. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.390964 · Cited by 67
Self-citation
Drug Delivery Across the Blood–Brain Barrier: A New Strategy for the Treatment of Neurological Diseases
Jiao, Y., Yang, L., Wang, R., Song, G., Fu, J., Wang, J., Gao, N., & Wang, H. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16121611 · Cited by 63
Unveiling the role of histone deacetylases in neurological diseases: focus on epilepsy
Cao, D., Zhou, X., Guo, Q., Xiang, M.-Y., Bao, M., He, B., & Mao, X. (2024) · Biomarker Research · doi:10.1186/s40364-024-00687-6 · Cited by 61
Recent advances in small molecular near-infrared fluorescence probes for a targeted diagnosis of the Alzheimer disease
Liu, Y., Zhuang, D., Wang, J., Huang, H., Li, R., Wu, C., Deng, Y., Hu, G., & Guo, B. (2022) · The Analyst · doi:10.1039/d2an01327d · Cited by 53
Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors
Keylor, M. H., Gulati, A., Kattar, S. D., Johnson, R., Chau, R., Margrey, K. A., Ardolino, M. J., Zárate, C., Poremba, K. E., Simov, V., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01968 · Cited by 46
A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment
Pelizzari‐Raymundo, D., Doultsinos, D., Pineau, R., Sauzay, C., Koutsandreas, T., Langlais, T., Carlesso, A., Gkotsi, E., Négroni, L., Avril, T., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106687 · Cited by 50
A novel NIR fluorescent probe for copper( ii ) imaging in Parkinson's disease mouse brain
Chen, J., Luo, R., Li, S., Shao, J., Wang, T., Xie, S., Xu, L., You, Q., Feng, S., & Feng, G. (2024) · Chemical Science · doi:10.1039/d4sc03445g · Cited by 42
Biomaterials in Traumatic Brain Injury: Perspectives and Challenges
Aqel, S., Al‐Thani, N. A., Haider, M. Z., Abdelhady, S., Thani, A. A. A., Kobeissy, F. H., & Shaito, A. A. (2023) · Biology · doi:10.3390/biology13010021 · Cited by 42
The risk associated with organophosphorus nerve agents: from their discovery to their unavoidable threat, current medical countermeasures and perspectives
Voros, C., Dias, J., Timperley, C. M., Nachon, F., Brown, R. C. D., & Baati, R. (2024) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2024.110973 · Cited by 44
Synergistic Modulation by Halogens and Pyridine Crossing the Blood–Brain Barrier for In Situ Visualization of Thiol Flux in the Epileptic Brain
Yang, Y.-T., Zhang, Y., Ma, M., Liu, H., Ge, K., Zhang, C., Jin, M., Liu, D., Wang, S., Yin, C., et al. (2022) · Analytical Chemistry · doi:10.1021/acs.analchem.2c03390 · Cited by 39
Myricetin Oligomer Triggers Multi-Receptor Mediated Penetration and Autophagic Restoration of Blood-Brain Barrier for Ischemic Stroke Treatment
Liu, L., Ma, Z., Han, Q., Meng, W., Wang, H., Guan, X., & Shi, Q. (2024) · ACS Nano · doi:10.1021/acsnano.3c09532 · Cited by 37
Intravenous administration of blood–brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system
Wang, C., Wang, S., Xue, Y., Zhong, Y., Li, H., Hou, X., Kang, D. D., Liu, Z., Tian, M., Wang, L., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02487-7 · Cited by 53
In Silico Study in MPO and Molecular Docking of the Synthetic Drynaran Analogues Against the Chronic Tinnitus: Modulation of the M1 Muscarinic Acetylcholine Receptor
da Rocha, M. N., da Fonseca, A. M., Dantas, A. N. M., dos Santos, H. S., Marinho, E. S., & Marinho, G. S. (2023) · Molecular Biotechnology · doi:10.1007/s12033-023-00748-5 · Cited by 36
Blood–brain barrier transporters: a translational consideration for CNS delivery of neurotherapeutics
Ronaldson, P. T., & Davis, T. P. (2024) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2024.2306138 · Cited by 41
Advances in nanoparticle-based therapeutics for ischemic stroke: Enhancing drug delivery and efficacy
Ji, P., Xu, Q., Li, J., Wang, Z., Mao, W., & Yan, P. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117564 · Cited by 35
Strategies for designing novel positron emission tomography (PET) radiotracers to cross the blood–brain barrier
Lindberg, A., Chassé, M., Varlow, C., Pees, A., & Vasdev, N. (2023) · Journal of Labelled Compounds and Radiopharmaceuticals · doi:10.1002/jlcr.4019 · Cited by 35
Computational Modeling of Pharmaceuticals with an Emphasis on Crossing the Blood–Brain Barrier
Alves, P. A., Camargo, L. C., de Souza, G. M., Mortari, M. R., & Homem-de-Mello, M. (2025) · Pharmaceuticals · doi:10.3390/ph18020217 · Cited by 35
Si-rhodamine fluorescent probe for monitoring of hypochlorous acid in the brains of mice afflicted with neuroinflammation
Liang, F., Jiang, J. H., Yang, X., Zhang, G., Zhou, J., Han, J., Geng, Y., & Wang, Z. (2022) · Chemical Communications · doi:10.1039/d2cc06475h · Cited by 32
Perspectives and new aspects of histone deacetylase inhibitors in the therapy of CNS diseases
Han, B. R., Wang, M., Li, J., Chen, Q., Sun, N., Yang, X., & Zhang, Q. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115613 · Cited by 32
Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action
Waris, A., Ullah, A., Asim, M., Ullah, R., Rafe, M. R., Bello, S. T., & Alhumaydhi, F. A. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1403232 · Cited by 30
Quinoline Quest: Kynurenic Acid Strategies for Next-Generation Therapeutics via Rational Drug Design
Tanaka, M., Szatmári, I., & Vécsei, L. (2025) · Pharmaceuticals · doi:10.3390/ph18050607 · Cited by 37
PROTACs in the Management of Prostate Cancer
Poornachandra, Y., Babalghith, A. O., Andra, V. V., & Syed, R. (2023) · Molecules · doi:10.3390/molecules28093698 · Cited by 31
Predicting In Vivo Compound Brain Penetration Using Multi-task Graph Neural Networks
Hamzic, S., Lewis, R. A., Desrayaud, S., Soylu, C., Fortunato, M., Gerebtzoff, G., & Rodríguez-Pérez, R. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.2c00412 · Cited by 30
Iterative Design of Near-Infrared Fluorescent Probes for Early Diagnosis of Alzheimer’s Disease by Targeting Aβ Oligomers
Liu, B., Li, X., Liu, Z., He, B., Xu, H., Cao, J., Zeng, F., Feng, H., Ren, Y., Li, H., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00252 · Cited by 27
Synthesis, in vitro and structural aspects of cap substituted Suberoylanilide hydroxamic acid analogs as potential inducers of apoptosis in Glioblastoma cancer cells via HDAC /microRNA regulation
Ramaiah, M. J., Ramalingam, P. S., Mathavan, S., Yamajala, R. B. R. D., Moparthi, N. R., Kurappalli, R. K., & Manyam, R. R. (2022) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2022.109876 · Cited by 27
The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain
Martos, D., Lőrinczi, B., Szatmári, I., Vécsei, L., & Tanaka, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063394 · Cited by 25
Furan-Derived Lipid Nanoparticles for Transporting mRNA to the Central Nervous System
Liu, Z., Zhang, Y., Li, H., Guo, K., Tian, M., Cao, D., Kang, D. D., Xue, Y., Hou, X., Wang, C., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c16326 · Cited by 26
A Computational Physics-based Approach to Predict Unbound Brain-to-Plasma Partition Coefficient, K p,uu
Lawrenz, M., Svensson, M., Kato, M., Dingley, K. H., Elk, J. C., Nie, Z., Zou, Y., Kaplan, Z., Lagiakos, H. R., Igawa, H., et al. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00150 · Cited by 27
Biomimetic membrane-coated nanoparticles specially permeate the inflammatory blood-brain barrier to deliver plasmin therapy for brain metastases
Zhao, M., Lin, Y., Zeng, Y., Lv, Z., Liang, J., Tang, P., Zhen, X., & Han, L. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.12.066 · Cited by 24
A BODIPY-based probe for amyloid-β imaging in vivo
Zhu, M., Zhang, G., Hu, Z., Zhu, C., Chen, Y., James, T. D., Ma, L., & Wang, Z. (2023) · Organic Chemistry Frontiers · doi:10.1039/d2qo02032g · Cited by 24
Self-citation
Cutting-edge advances in modeling the blood–brain barrier and tools for its reversible permeabilization for enhanced drug delivery into the brain
Sharma, A., Fernandes, D. C., Reis, R. L., Gołubczyk, D., Neumann, S., Łukomska, B., Janowski, M., Kortylewski, M., Walczak, P., Oliveira, J. M., et al. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01079-3 · Cited by 26
Synthesis, computational and antimicrobial study of 2-(2-Hydrazinyl)thiazole derivatives
Shinde, R. A., Adole, V. A., & Jagdale, B. S. (2023) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2023.137096 · Cited by 23
Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action
Wilhelmsen, K., Deshpande, A., Tronnes, S. U., Mahanta, M., BANICKI, M., COCHRAN, M., Cowdin, S., Fortney, K., Hartman, G. D., Hughes, R. E., et al. (2025) · The Journal of Experimental Medicine · doi:10.1084/jem.20242403 · Cited by 22
Self-citation
Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease
Yu, C., Liu, X., Ma, B., Xu, J., Chen, Y., Dai, C., Peng, H., & Zha, D. (2024) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2024.2313682 · Cited by 22
Self-citation
Galantamine-memantine hybrids for Alzheimer's disease: The influence of linker rigidity in biological activity and pharmacokinetic properties
Basagni, F., Ortega, J. A., Bertozzi, S. M., Armirotti, A., Summa, M., Bertorelli, R., Bartolini, M., Mellor, I. R., Bedeschi, M., Bottegoni, G., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115803 · Cited by 22
CMGN: a conditional molecular generation net to design target-specific molecules with desired properties
Yang, M., Sun, H., Liu, X., Xue, X., Deng, Y., & Wang, X. (2023) · Briefings in Bioinformatics · doi:10.1093/bib/bbad185 · Cited by 22
Self-citation
Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer
Hill, J., Jones, R. M., & Crich, D. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01669 · Cited by 21
Direct Synthesis of α- and β-2′-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation
Tang, X., Zhou, Y., Wang, Y., Lin, Y., Pan, S., Che, Q., Sang, J., Gao, Z., Zhang, W., Wang, Y., et al. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c01780 · Cited by 21
Self-citation
NLRP1 inflammasome in neurodegenerative disorders: From pathology to therapies
Zhang, M.-J., Yang, L., Li, Z.-Y., Zhou, L.-Y., Wang, Y.-J., Wang, H.-S., Cui, X.-J., & Yao, M. (2024) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2024.10.004 · Cited by 21
Self-citation
Challenges and material innovations in drug delivery to central nervous system tumors
Gong, Z., Zhou, D., Wu, D., Han, Y., Yu, H. Q., Shen, H., Feng, W., Hou, L., Chen, Y., & Xu, T. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123180 · Cited by 23
Self-citation
Exploring the neuroplasticity hypothesis in depression: The role of traditional Chinese herbal medicine
Zeng, J., Wang, Z., Zhang, X., Zhao, A., Qi, H., Jiang, Y., Cai, D., & Zeng, N. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156927 · Cited by 21
Development of novel near-infrared GFP chromophore-based fluorescent probes for imaging of amyloid-β plaque and viscosity
Guo, Y., Leng, H., Chen, Q., Su, J., Shi, W., Xia, C., Zhang, L., & Yan, J. (2022) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2022.132648 · Cited by 20
Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis
Chen, X., Wu, T., Du, Z., Kang, W., Xu, R., Meng, F., Liu, C., Chen, Y., Bao, Q., Shen, J., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.116080 · Cited by 21
Self-citation
Discovery of 4-benzylpiperazinequinoline BChE inhibitor that suppresses neuroinflammation for the treatment of Alzheimer's disease
Chen, Y., Zhang, W., Li, Q., Xie, H., Xing, S., Lü, X., Lyu, W., Xiong, B., Wang, Y., Qu, W., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116463 · Cited by 20
Self-citation
Applications of hydrogels and nanoparticles in the treatment of traumatic brain injury
Shi, J., Tang, J., Jin, X., Jiang, N., Yang, Y., Chen, H., Han, Y., & Fu, X. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1515164 · Cited by 21
Simultaneous Imaging of pH and Peroxynitrite in the Endoplasmic Reticulum and Mitochondria: Revealing Organelle Interactions in Alzheimer’s Disease Pathogenesis
Huang, L., Ma, L., Zhao, Q., Zhu, Q., She, G., Mu, L., & Shi, W. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.4c03646 · Cited by 18
Application of Novel Drug‐Delivery Strategies in Neurological Disorders
Li, C., Yao, S., Li, Z., & Gao, Y. (2025) · Advanced Materials · doi:10.1002/adma.202503646 · Cited by 21
The role of exosomes in central nervous system tissue regeneration and repair
Wang, J., & Yang, L. (2023) · Biomedical Materials · doi:10.1088/1748-605x/ace39c · Cited by 19
CNS delivery of targeted protein degraders
Agarwal, P., Reid, D. L., & Amiji, M. M. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.06.057 · Cited by 19
Selective Covalent Inhibiting JNK3 by Small Molecules for Parkinson's Diseases
Wen, S., Yang, P., Xiao, H., Zhu, Y., Bu, F., Wang, A., Sun, Q., Wang, G., & Ouyang, L. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202411037 · Cited by 17
Smart micro/nanorobots for drug delivery in the brain
Shi, D., Wang, X., Deng, Y., Zhou, H., Wang, Y., Chu, P. K.-H., & Li, J. (2025) · Progress in Materials Science · doi:10.1016/j.pmatsci.2025.101533 · Cited by 17
Self-citation
Histone deacetylase 6 inhibitors with blood-brain barrier penetration as a potential strategy for CNS-Disorders therapy
Gu, X. Q., Zhang, H., Jiao, M.-R., Han, B. R., Zhang, Z., Li, J., & Zhang, Q. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.114090 · Cited by 18
In silico Prediction of ADMET/Drug-likeness Properties of Bioactive Phloroglucinols from Hypericum Genus
da Silva, C. P. M., das Neves, G. M., von Poser, G. L., Eifler-Lima, V. L., & Rates, S. M. K. (2023) · Medicinal Chemistry · doi:10.2174/1573406419666230601092358 · Cited by 18
Real-Time Monitoring of Tyrosine Hydroxylase Activity with a Ratiometric Fluorescent Probe
Yao, J., Li, L., Xu, J., Liu, Y., Shi, J., Yu, X., Kong, Q., & Li, K. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.4c00382 · Cited by 17
Recent progress on nanotechnologies for enhancing blood‐brain barrier permeability
Liu, Q., Chen, Z., Guiseppi‐Elie, A., Meng, F., & Luo, L. (2025) · Smart Molecules · doi:10.1002/smo.20240052 · Cited by 20
Targeting BRD4 and PI3K signaling pathways for the treatment of medulloblastoma
Sethi, B., Kumar, V., Jayasinghe, T. D., Dong, Y., Ronning, D. R., Zhong, H. A., Coulter, D. W., & Mahato, R. I. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.12.055 · Cited by 16
An ultrasound-activated piezoelectric sonosensitizer enhances mitochondrial depolarization for effective treatment of orthotopic glioma
Huang, X., Gao, L., Ge, W., Li, S., Liu, Y., Fan, X., Tu, S., & Wang, F. (2024) · Acta Biomaterialia · doi:10.1016/j.actbio.2024.10.051 · Cited by 16
Advancing CNS Therapeutics: Enhancing Neurological Disorders with Nanoparticle-Based Gene and Enzyme Replacement Therapies
Liu, S., Li, H., Xi, S., Zhang, Y., & Sun, T. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s457393 · Cited by 16
A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors
Liang, R., Tomita, D., Sasaki, Y., Ginn, J. D., Michino, M., Huggins, D. J., Baxt, L. A., Kargman, S., Shahid, M., Aso, K., et al. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00448 · Cited by 15
Near-infrared II theranostic agents for the diagnosis and treatment of Alzheimer’s disease
Zhou, C., Zeng, F., Yang, H., Liang, Z., Xu, G., Li, X., Liu, X., & Yang, J. (2024) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-024-06690-1 · Cited by 14
Nanoparticles targeting the central circadian clock: Potential applications for neurological disorders
Meur, M. L., Pignatelli, J., Blasi, P., & Palomo, V. (2025) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2025.115561 · Cited by 15
MoleculeFormer is a GCN-transformer architecture for molecular property prediction
Qin, M., Sun, Z., Feng, L., Han, C., Xia, J., & Han, L. (2025) · Communications Biology · doi:10.1038/s42003-025-09064-x · Cited by 16
Small‐Molecule Regulators for Gene Switches to Program Mammalian Cell Behaviour
Mansouri, M., & Fussenegger, M. (2023) · ChemBioChem · doi:10.1002/cbic.202300717 · Cited by 14
Targeted strategies to deliver boron agents across the blood–brain barrier for neutron capture therapy of brain tumors
Lan, G., Song, Q., Luan, Y., & Cheng, Y. (2023) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2023.123747 · Cited by 14
Nasal nanotherapeutics for central nervous system disorders: Bridging the translational gap in central nervous system drug delivery
Zhang, Y.-B., Liu, M., Wang, Y., Hu, D., Wu, S., Zhao, B., Zhou, B., & Yang, L. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177958 · Cited by 14
Self-citation
Peering into the Brain’s Estrogen Receptors: PET Tracers for Visualization of Nuclear and Extranuclear Estrogen Receptors in Brain Disorders
Arjmand, S., Bender, D., Jakobsen, S., Wegener, G., & Landau, A. M. (2023) · Biomolecules · doi:10.3390/biom13091405 · Cited by 13
Opportunities and perspectives of small molecular phosphodiesterase inhibitors in neurodegenerative diseases
Li, Q., Liao, Q., Qi, S., Huang, H., He, S., Lyu, W., Liang, J., Qin, H., Cheng, Z., Fan, Y., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116386 · Cited by 13
Self-citation
A 3D generation framework using diffusion model and reinforcement learning to generate multi-target compounds with desired properties
Yuan, Y., Pan, X., Li, X., Zhang, R., & Su, W. (2025) · Journal of Cheminformatics · doi:10.1186/s13321-025-01035-y · Cited by 17
Generation of a Pure Culture of Neuron-like Cells with a Glutamatergic Phenotype from Mouse Astrocytes
Fernandes, G. S., Singh, R. D., & Kim, K. K. (2022) · Biomedicines · doi:10.3390/biomedicines10040928 · Cited by 13
First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod
Starke, L., Millward, J. M., Prinz, C., Sherazi, F., Waiczies, H., Lippert, C., Nazaré, M., Paul, F., Niendorf, T., & Waiczies, S. (2023) · Theranostics · doi:10.7150/thno.77041 · Cited by 12
Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy
Faridoon, F., Zheng, J., Zhang, T., Tong, S., Liu, T., Cui, J., Haojie, X., Hu, D., Shen, Y., Yin, Y., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00552 · Cited by 12
Group graph: a molecular graph representation with enhanced performance, efficiency and interpretability
Cao, P.-Y., He, Y., Cui, M.-Y., Zhang, X., Zhang, Q., & Zhang, H. (2024) · Journal of Cheminformatics · doi:10.1186/s13321-024-00933-x · Cited by 14
Advances in Molecular Imaging of VEGFRs: Innovations in Imaging and Therapeutics
Karimi, H., Lee, S., Xu, W., Langhans, S. A., Johnson, D. K., Stauff, E., Kecskemethy, H. H., Averill, L. W., & Yue, X. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115373 · Cited by 12
Target-Agnostic P-Glycoprotein Assessment Yields Strategies to Evade Efflux, Leading to a BRAF Inhibitor with Intracranial Efficacy
Kelly, A. M., Berry, M. R., Tasker, S. Z., McKee, S. A., Fan, T. M., & Hergenrother, P. J. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c03944 · Cited by 14
Preclinical Development of the Na-K-2Cl Co-transporter-1 (NKCC1) Inhibitor ARN23746 for the Treatment of Neurodevelopmental Disorders
Savardi, A., Malizia, A. P., Vivo, M. D., Cancedda, L., & Borgogno, M. (2023) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.2c00197 · Cited by 13
Molecular Windows into the Brain: Advances in BBB-Penetrable NIR Fluorescent Imaging Probes
Niu, H., Xue, X., Xu, M., Sun, B., Li, S., Xie, M., Long, X., & Wang, S. (2025) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.5c09651 · Cited by 12
Polymeric nanotherapeutics: An emerging therapeutic approach for the management of neurodegenerative disorders
Chakraborty, P., Bhattacharyya, C., Sahu, R., Dua, T. K., Kandimalla, R. J. L., & Dewanjee, S. (2023) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2023.105267 · Cited by 12
BODIPY‐Based Small‐Molecule Photoacoustic Probes for Biomedical Imaging
Song, K., Gao, H., Wang, X., & Liu, Z. (2024) · ChemPhotoChem · doi:10.1002/cptc.202400335 · Cited by 11
Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET
Schlein, E., Rokka, J., Odell, L. R., van den Broek, S. L., Herth, M. M., Battisti, U. M., Syvänen, S., Sehlin, D., & Eriksson, J. (2024) · EJNMMI Radiopharmacy and Chemistry · doi:10.1186/s41181-024-00250-6 · Cited by 10
De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases
Kieliszek, A., Mobilio, D., Bassey-Archibong, B. I., Johnson, J. W., Piotrowski, M. L., de Araujo, E. D., Sedighi, A., Aghaei, N., Escudero, L., Ang, P., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101755 · Cited by 10
Historical perspectives and recent advances in small molecule ligands of selective/biased/multi-targeted μ/δ/κ opioid receptor (2019–2022)
He, Y., Su, Q., Zhao, L., Zhang, L., Lu, Y., & Shi, J. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106869 · Cited by 10
An Overview of Nanocapsule and Lipid Nanocapsule: Recent Developments and Future Prospects
Elmarzugi, N. A., Amara, R. O., Eshmela, M., & Eid, A. M. (2023) · Palestinian medical and pharmaceutical journal/Palestinian medical & pharmaceutical journal · doi:10.59049/2790-0231.1244 · Cited by 10
Pharmacological modulation of chloride channels as a therapeutic strategy for neurological disorders
Wang, Z., & Choi, K. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1122444 · Cited by 9
Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations
Thomson, C., Bartoň, P., Braybrooke, E. L., Colclough, N., Dong, Z., Evans, L., Floc’h, N., Guerot, C. M., Hargreaves, D., Khurana, P., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00227 · Cited by 9
Design, synthesis, and anticancer evaluation of alkynylated pyrrole derivatives
Wei, H., Cao, Y., Zhao, C., Shao, Z., Huo, X., Pan, J., & Zhuang, R. (2024) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14484 · Cited by 8
Interactions between hydroxylated polycyclic aromatic hydrocarbons and serum albumins: multispectral and molecular docking analyses
Li, M., Zhang, J., Zhu, Y., & Zhang, Y. (2022) · Luminescence · doi:10.1002/bio.4384 · Cited by 8
Novel 4-Aryl-4H-chromene derivative displayed excellent in vivo anti-glioblastoma efficacy as the microtubule-targeting agent
Yang, H., Zhang, D., Yuan, Z., Qiao, H., Xia, Z., Cao, F., Lu, Y., & Jiang, F. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116205 · Cited by 8
Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators
Tangallapally, R. P., Subramanian, C., Yun, M., Edwards, A., Sharma, L. K., Yang, L., Creed, K., Wang, J., Jackowski, S., Rock, C. O., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01211 · Cited by 7
Breaking barriers: Medicinal chemistry strategies and advanced in-silico approaches for overcoming the BBB and enhancing CNS penetration
Ajayi, E. D., Elazazy, M., Abouzid, K. A. M., & Ali, H. I. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118219 · Cited by 9
Biodegradable lipid nanoparticles for genome editing in the brain via intrathecal administration
Dong, S., Healy, L., Gong, F., Xu, Y., Cai, Y., Solek, N. C., Chen, J., Zhou, M., Thomson, T., Savguira, M., et al. (2025) · Materials Today · doi:10.1016/j.mattod.2025.11.032 · Cited by 9
Engineering brain-penetrant PROTACs: Bridging molecular design and CNS delivery
Li, X., Li, J., Sun, Y., Yao, T., Lu, Y., Liu, S., Li, H., Shi, Y., Chen, L., Zhao, Y., et al. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115876 · Cited by 8
Design, synthesis, and biological evaluation of novel spirocyclic compounds as potential anti-glioblastoma agents
Zhu, H., Song, X., Pan, Y., Li, M., Chen, L., Xiao, P., Du, R., Dong, Z., & Yang, C. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115595 · Cited by 8
Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging
Dutta, N., Gerke, J. A., Odron, S. F., Morris, J. D., Hruby, A. J., Kim, J., Torres, T. C., Shemtov, S. J., Clarke, J. G., Chang, M. C., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01144-w · Cited by 6
Progress of research in the application of ultrasound technology for the treatment of Alzheimer’s disease
Cai, Q., Meng, L., Quan, M., Wang, L., Ren, J., Zheng, C., Yang, J., & Ming, D. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00539 · Cited by 8

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
ORCID: Wang, Yuanyuan
Chen, Ying
Xing, Shuaishuai
Chen, Yao
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
DOI: 10.1021/acs.jmedchem.1c00910
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: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks