The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Design, Synthesis, and Evaluation of Orally Bioavailable Quinoline–Indole Derivatives as Innovative Multitarget-Directed Ligands: Promotion of Cell Proliferation in the Adult Murine Hippocampus for the Treatment of Alzheimer’s Disease
Abstract
A novel series of quinoline-indole derivatives were synthesized and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease (AD). Biological evaluation revealed that the derivatives had multifunctional profiles including antioxidant effects, blood-brain barrier (BBB) penetration, biometal chelation, Aβ aggregation modulation, neurotrophic and neuroprotective properties. Moreover, several representative target derivatives demonstrated hippocampal cell proliferation in living adult mice by intracerebroventricular (icv) injection or oral administration. Further drug-like property analysis demonstrated that the optimized compound, 8d (WI-1758), had liver microsomal metabolic stability, was well tolerated (>2000 mg/kg), and had a rational pharmacokinetic profile, as well as an oral bioavailability of 14.1% and a positive log BB (-0.19) to cross the BBB in vivo. Pharmacodynamics studies demonstrated that chronic oral administration of 8d·HCl substantially ameliorated the cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral β-amyloid deposits.
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“Interestingly, among those small molecules, indole-based melatonin-N-benzylamine hybrids, have been proven to effectively promote the development of neural stem cells into neuronal phenotypes.128”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [128]
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1 retracted
Ranković, Z. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01469 · Cited by 97
RetractedAlzheimer’s disease: Clinical trials and drug development
Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., & Kivipelto, M. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70119-8 · Cited by 1,217
High throughput artificial membrane permeability assay for blood–brain barrier
Di, L., Kerns, E. H., Fan, K., McConnell, O. J., & Carter, G. T. (2003) · European Journal of Medicinal Chemistry · doi:10.1016/s0223-5234(03)00012-6 · Cited by 1,195
(2016) · London School of Economics and Political Science Research Online (London School of Economics and Political Science) · Cited by 874
Adlard, P. A., Cherny, R. A., Finkelstein, D. I., Gautier, E., Robb, E., Cortes, M., Volitakis, I., Liu, X., Smith, J. P., Perez, K., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.06.018 · Cited by 672
Fluoxetine targets early progenitor cells in the adult brain
Encinas, J. M., Vaahtokari, A., & Enikolopov, G. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601992103 · Cited by 637
CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure
Ranković, Z. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501535r · Cited by 592
A regenerative approach to the treatment of multiple sclerosis
Deshmukh, V. A., Tardif, V., Lyssiotis, C. A., Green, C. C., Kerman, B., Kim, H. J., Padmanabhan, K., Swoboda, J. G., Ahmad, I., Kondo, T., et al. (2013) · Nature · doi:10.1038/nature12647 · Cited by 531
Biological metals and metal-targeting compounds in major neurodegenerative diseases
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Wohnsland, F., & Faller, B. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm001020e · Cited by 495
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Metadata
- Authors
- Wang, Z., Hu, J., Yang, X., Feng, X., Li, X., Huang, L., & Chan, A. S. C.
- Affiliations
- Sun Yat-sen University (CN)
- Hunan Normal University (CN)
- Corresponding author
- Li, Xingshu
- Huang, Ling
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-02-08
- Volume
- 61
- Issue
- 5
- Pages
- 1871-1894
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2786700855
- Cited by
- 91
- References
- 49
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 19 · 2019: 13 · 2018: 5
- FWCI
- 9.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education of the People's Republic of China (15ykpy04)
- National Natural Science Foundation of China (21302235, 21772241)
- Natural Science Foundation of Guangdong Province (2014A030313124)
- Guangzhou Municipality (201610010111)
- Government Province (2015TQ01R244)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- multi-target-directed ligands, Alzheimer's disease, oral bioavailability, blood-brain barrier penetration, amyloid-beta aggregation, antioxidant activity, neuroprotection, neurotrophic activity, hippocampal cell proliferation, cognitive impairment, spatial memory, APP/PS1 mice, drug-likeness, pharmacokinetics, pharmacodynamics
- MeSH terms
- Alzheimer Disease, Animals, Blood-Brain Barrier, Hippocampus, Humans, Indoles, Ligands, Memory Disorders, Quinolines, Drug Design, Amyloid beta-Peptides, Cell Proliferation, Mice
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