Advanced prodrug approaches for neurodegenerative diseases

Authors

DOI:

https://doi.org/10.14295/bjs.v2i10.369

Keywords:

Alzheimer's disease, biotransformation, multiple sclerosis, prodrugs, pharmacokinetic

Abstract

The prodrug technique is still one of the most effective ways to increase hydrophilic substances' medicinal, pharmacodynamic and pharmacokinetic properties. Prodrugs produced in current history have shown good pharmacokinetic characteristics, allowing for a more consistent release and fewer changes in plasma levels. Developing new prodrugs having a desirable ADME (Absorption Distribution Metabolism and Elimination) properties and that still can cross the Blood brain barrier (BBB) and pharmacologically active an appealing task for medicinal chemists. The loss of brain neuron activity characterizes neurodegenerative illnesses, resulting in progressive Gradual cognitive impairment (GCI). Some of the common neurodegenerative diseases are PD (Parkinson's disease), AD (Alzheimer's disease), MS (Multiple sclerosis), ALS (amyotrophic lateral sclerosis) & HD (Huntington's disease) are examples of neurodegenerative illnesses with a variety of etiologies and morphological and pathophysiological aspects. The current review is concerned with current advances in prodrug approaches for the treatment and prevention of the most prevalent neurological illnesses, as well as their absorption, selective CNS targeting and chemical and enzymatic stability.

References

Albert, A. (1958). Chemical aspects of selective toxicity. Nature, 182(4633), 421-423. https://doi.org/10.1038/182421a0 DOI: https://doi.org/10.1038/182421a0

Athar, T., Al Balushi, K., & Khan, S. A. (2021). Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease. Molecular Biology Reports, 48(7), 5629-5645. https://doi.org/10.1007/s11033-021-06512-9 DOI: https://doi.org/10.1007/s11033-021-06512-9

Atlas, D. (2016). DopAmide: novel, water-soluble, slow-release l-dihydroxyphenylalanine (l-DOPA) precursor moderates l-DOPA conversion to dopamine and generates a sustained level of dopamine at dopaminergic neurons. CNS Neuroscience & Theraoeuthics, 22(6), 461-467. https://doi.org/10.1111/cns.12518 DOI: https://doi.org/10.1111/cns.12518

Ashraghi, M. R., Pagano, G., Polychronis, S., Niccolini, F., & Politis, M. (2016). Parkinson’s disease, diabetes and cognitive impairment. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, 10(1), 11-21. https://www.ingentaconnect.com/content/ben/emi/2016/00000010/00000001/art00004 DOI: https://doi.org/10.2174/1872214810999160628105549

Benek, O., Korabecny, J., & Soukup, O. (2020). A perspective on multi-target drugs for Alzheimer’s disease. Trends in Pharmacological Sciences, 41(7), 434-45. https://doi.org/10.1016/j.tips.2020.04.008 DOI: https://doi.org/10.1016/j.tips.2020.04.008

Bianchi, V. E., Herrera, P. F., & Laura, R. (2021). Effect of nutrition on neurodegenerative diseases. A systematic review. Nutritional neuroscience, 24(10), 810-834. https://doi.org/10.1080/1028415X.2019.1681088 DOI: https://doi.org/10.1080/1028415X.2019.1681088

Brooks, D. J., & Sagar, H. (2003). Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomised, placebo controlled, double blind, six month study. Journal of Neurology, Neurosurgery & Psychiatry, 74(8), 1071-1079. http://dx.doi.org/10.1136/jnnp.74.8.1071 DOI: https://doi.org/10.1136/jnnp.74.8.1071

Caruso, G., Caraci, F., & Jolivet, R. B. (2019). Pivotal role of carnosine in the modulation of brain cells activity: Multimodal mechanism of action and therapeutic potential in neurodegenerative disorders. Progress in Neurobiology, 175, 35-53. https://doi.org/10.1016/j.pneurobio.2018.12.004 DOI: https://doi.org/10.1016/j.pneurobio.2018.12.004

Chen, Q., Gong, T., Liu, J., Wang, X., Fu, H., & Zhang, Z. (2009). Synthesis, in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery. Journal of Drug Targeting, 17(4), 318-328. https://doi.org/10.1080/10611860902795399 DOI: https://doi.org/10.1080/10611860902795399

Chen, C., Wang, Z., Zhang, Z., Liu, X., Kang, S. S., Zhang, Y., & Ye, K. (2018). The prodrug of 7, 8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proceedings of the National Academy of Sciences, 115(3), 578-583. https://doi.org/10.1073/pnas.1718683115 DOI: https://doi.org/10.1073/pnas.1718683115

Corbett, A, & Ballard, C. (2012). New and emerging treatments for Alzheimer’s disease. Expert Review of Neurotherapeutics, 12(5), 535-543. https://doi.org/10.1586/ern.12.43 DOI: https://doi.org/10.1586/ern.12.43

Deguchi, Y., Hayashi, H., Fujii, S., Naito, T., Yokoyama, Y., Yamada, S., & Kimura, R. (2000). Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for the therapy of Alzheimer's disease. Journal of Drug Targeting, 8(6), 371-381. https://doi.org/10.3109/10611860008997913 DOI: https://doi.org/10.3109/10611860008997913

Fernández, M., Barcia, E., Fernández-Carballido, A., Garcia, L., Slowing, K., & Negro, S. (2012). Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson’s disease. International Journal of Pharmaceutics, 438(1-2), 266-278. https://doi.org/10.1016/j.ijpharm.2012.09.024 DOI: https://doi.org/10.1016/j.ijpharm.2012.09.024

Giacobini, E., & Gold, G. (2013). Alzheimer disease therapy-moving from amyloid-β to tau. Nature Reviews Neurology, 9(12), 677-686. https://doi.org/10.1038/nrneurol.2013.223 DOI: https://doi.org/10.1038/nrneurol.2013.223

Goldstein, D. S., Holmes, C., Sewell, L. (2011). Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS. The Journal of Clinical Pharmacology, 51(1), 66-74. https://doi.org/10.1177/0091270010363476 DOI: https://doi.org/10.1177/0091270010363476

Gonzalez, F. (2009). Diphenhydramine may be useful as a palliative treatment for patients dying with Parkinson’s disease and tremors: a case report and discussion. American Journal of Hospice & Palliative Medicine, 26(6), 474-475. 10.1177/1049909109338937 DOI: https://doi.org/10.1177/1049909109338937

Han, H. K., & Amidon, G. L. (2000). Targeted prodrug design to optimize drug delivery. Aaps Pharmsci, (1), 48-58. https://doi.org/10.1208/ps020106 DOI: https://doi.org/10.1208/ps020106

Hey, J. A., Jeremy, Y. Y., Versavel, M., Abushakra, S., Kocis, P., Power, A., Kaplan, P. L., Amedio, J., & Tolar, M. (2018). Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clinical Pharmacokinetics, 57(3), 315-333. https://doi.org/10.1007/s40262-017-0608-3 DOI: https://doi.org/10.1007/s40262-017-0608-3

Jellinker, K. A. (2003). General aspects of neurodegeneration. Journal of Neural Transmission, 65, 101-144. https://doi.org/10.1007/978-3-7091-0643-3_7 DOI: https://doi.org/10.1007/978-3-7091-0643-3_7

Jellinger, K. A. (2010). Basic mechanisms of neurodegeneration: a critical update. Journal of Cellular and Molecular Medicine, 14(3), 457-487. https://doi.org/10.1111/j.1582-4934.2010.01010.x DOI: https://doi.org/10.1111/j.1582-4934.2010.01010.x

Kianirad, Y., & Simuni, T. (2016). Novel approaches to optimization of levodopa therapy for Parkinson’s disease. Current Neurology and Neuroscience Reports, 16. https://doi.org/10.1007/s11910-016-0635-8 DOI: https://doi.org/10.1007/s11910-016-0635-8

Lardenoije, R., van den Hove, D. L. A., Havermans, M., van Casteren, A., Le, K. X., & Palmour, R. (2018). Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer’s disease. Molecular and Cellular Neuroscience, 86, 1-15. https://doi.org/10.1016/j.mcn.2017.11.002 DOI: https://doi.org/10.1016/j.mcn.2017.11.002

Lima, L., Pereira, S., Junior, R., Santos, F., Nascimento, A., Feitosa, C. (2018). A brief review on the neuroprotective mechanism of vitexin. BioMed Research International, 2018, 1-8. https://doi.org/10.1155/2018/4785089 DOI: https://doi.org/10.1155/2018/4785089

Mannila, A., Rautio, J., Lehtonen, M., Järvinen, T., & Savolainen, J. (2005). Inefficient central nervous system delivery limits the use of ibuprofen in neurodegenerative diseases. European journal of pharmaceutical sciences, 24(1), 101-105. https://doi.org/10.1016/j.ejps.2004.10.004 DOI: https://doi.org/10.1016/j.ejps.2004.10.004

Marsden, C. D., Parkes, J. D., & Rees, J. E. (1973). A year’s comparison of treatment of patients with Parkinson’s disease with levodopa combined with carbidopa versus treatment with levodopa alone. Lancet, 302(7844), 1459-1462. https://doi.org/10.1016/S0140-6736(73)92729-3 DOI: https://doi.org/10.1016/S0140-6736(73)92729-3

McBride, J. L., Behrstock, S. P., Chen, E. Y., Jakel, R. J., Siegel, I., Svendsen, C. N., & Kordower, J. H. (2004). Human neural stem cell transplants improve motor function in a rat model of Huntington's disease. Journal of Comparative Neurology, 475(2), 211-219. https://doi.org/10.1002/cne.20176 DOI: https://doi.org/10.1002/cne.20176

Melo, A., Monteiro, L., Lima, R. M. F., de Oliveira, D. M., de Cerqueira, M. D., & El-Bachá, R. S. (2011). Oxidative stress in neurodegenerative diseases: mechanism and therapeutic perspectives. Oxidative Medicine and Cellular Longevity, 2011, 1-14. https://doi.org/10.1155/2011/467180 DOI: https://doi.org/10.1155/2011/467180

Müller ,T. (2015). Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Drugs, 75, 157-174. https://doi.org/10.1007/s40265-014-0343-0 DOI: https://doi.org/10.1007/s40265-014-0343-0

Müller, M. L. T. M., & Bohnen, N. I. (2013). Cholinergic dysfunction in Parkinson’s disease. Current Neurology and Neuroscience Reports, 13(9), 377. https://doi.org/10.1007/s11910-013-0377-9 DOI: https://doi.org/10.1007/s11910-013-0377-9

Nazarenko, I. V., MSh, Z., Volkov, A. V., Kamenskiĭ, A. A., & RKh, Z. (1999). Functional-morphologic evaluation of the effect of the regulatory peptide kyotorphin on the status of the CNS in the post-resuscitation period. Patologicheskaia Fiziologiia i Eksperimental'naia Terapiia, 1(2), 31-33. https://europepmc.org/article/med/10379182

Novakova, I., Subileau, E. A., Toegel, S., Gruber, D., Lachmann, B., Urban, E., Chesne, C., Noe, C. R., & Neuhaus, W. (2014). Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models. PloS One, 9(1), e86806. https://doi.org/10.1371/journal.pone.0086806 DOI: https://doi.org/10.1371/journal.pone.0086806

Pasinetti, G. M., & Aisen, P. S. (1998). Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain. Neuroscience, 87(2), 319-324. https://doi.org/10.1016/S0306-4522(98)00218-8 DOI: https://doi.org/10.1016/S0306-4522(98)00218-8

Pignatello, R., Pantò, V., Salmaso, S., Bersani, S., Pistarà, V., & Keep, V. (2008). Flurbiprofen derivatives in Alzheimer’s disease: Synthesis, pharmacokinetic and biological assessment of lipoamino acid prodrugs. Bioconjugate Chemistry, 19(1), 349-357. https://doi.org/10.1021/bc700312y DOI: https://doi.org/10.1021/bc700312y

Poewe, W., Seppi, K., Tanner, C. M., Halliday, G. M., Brundin, P., Volkmann, J., Schrag, A-E., & Lang, A. E. (2017). Parkinson disease. Nature Reviews Disease Primers, 3. https://doi.org/10.1038/nrdp.2017.13 DOI: https://doi.org/10.1038/nrdp.2017.13

Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., & Savolainen, J. (2008). Prodrugs: design and clinical applications. Nature reviews Drug discovery, 7(3), 255-70. https://doi.org/10.1038/nrd2468 DOI: https://doi.org/10.1038/nrd2468

Rinne, U., & Mölsä, P. (1979). Levodopa with benserazide or carbidopa in Parkinson disease. Neurology, 29(12), 1584-1589. https://doi.org/10.1212/WNL.29.12.1584 DOI: https://doi.org/10.1212/WNL.29.12.1584

Roy, R., Deb, J., Jana, S. S., & Dastidar, P. (2014). Peptide conjugates of a nonsteroidal anti-inflammatory drug as supramolecular gelators: Synthesis, characterization, and biological studies. Chemistry An Asian Journal, 9(11), 3196-3206. https://doi.org/10.1002/asia.201402672 DOI: https://doi.org/10.1002/asia.201402672

Santos, S. S., Santos, S. M., Pinto, A. R., Ramu, V. G., Heras, M., Bardaji, E., Tavares, I., & Castanho, M. A. (2016). Amidated and ibuprofen-conjugated kyotorphins promote neuronal rescue and memory recovery in cerebral hypoperfusion dementia model. Frontiers in aging neuroscience, 8. https://doi.org/10.3389/fnagi.2016.00001 DOI: https://doi.org/10.3389/fnagi.2016.00001

Savica, R., Grossardt, B. R., Bower, J. H. (2013). Incidence and pathology of synucleinopathies and tauopathies related to Parkinsonism. JAMA Neurology, 70(7), 859-866. https://jamanetwork.com/journals/jamaneurology/article-abstract/1688412 DOI: https://doi.org/10.1001/jamaneurol.2013.114

Saydoff, J. A., Liu, L. S., Garcia, R. A., Hu, Z., Li, D., & von Borstel, R. W. (2003). Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model of Huntington's disease. Brain research, 994(1), 44-54. https://doi.org/10.1016/j.brainres.2003.09.049 DOI: https://doi.org/10.1016/j.brainres.2003.09.049

Sestito, S., Daniele, S., Pietrobono, D., Citi, V., Bellusci, L., Chiellini, G., Calderone, V., Martini, C., & Rapposelli, S. (2019). Memantine prodrug as a new agent for Alzheimer’s Disease. Scientific Reports, 9(1), 1-1. https://doi.org/10.1038/s41598-019-40925-8 DOI: https://doi.org/10.1038/s41598-019-40925-8

Sinkula, A. A., & Yalkowsky, S. H. (1975). Rationale for design of biologically reversible drug derivatives: prodrugs. Journal of pharmaceutical sciences, 64(2), 181-210. https://doi.org/10.1002/jps.2600640203 DOI: https://doi.org/10.1002/jps.2600640203

Tampio, J., Huttunen, J., Montaser, A., & Huttunen, K. M. (2020). Targeting of perforin inhibitor into the brain parenchyma via a prodrug approach can decrease oxidative stress and neuroinflammation and improve cell survival. Molecular Neurobiology, 57(11), 4563-4577. https://doi.org/10.1007/s12035-020-02045-7 DOI: https://doi.org/10.1007/s12035-020-02045-7

Tutone, M., Chinnici, A., Almerico, A. M., Perricone, U., Sutera, F. M., & De Caro, V. (2016). Design, synthesis and preliminary evaluation of dopamine-amino acid conjugates as potential D1 dopaminergic modulators. European Journal of Medicinal Chemistry, 124, 435-444. https://doi.org/10.1016/j.ejmech.2016.08.051 DOI: https://doi.org/10.1016/j.ejmech.2016.08.051

Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T. D., Mazur, M., & Telser, J. (2007). Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry and Cell Biology, 39(1), 44-84. https://doi.org/10.1016/j.biocel.2006.07.001 DOI: https://doi.org/10.1016/j.biocel.2006.07.001

Xilouri, M., Brekk, O. R., & Stefanis, L. (2012). Alpha-synuclein and protein degradation systems: a reciprocal relationship. Molecular Neurobiology, 47, 537-551. https://doi.org/10.1007/s12035-012-8341-2 DOI: https://doi.org/10.1007/s12035-012-8341-2

Zhang, Q., Liang, Z., Chen, L. Y., Sun, X., Gong, T., & Zhang Z. R. (2012). Novel brain targeting prodrugs of naproxen based on dimethylamino group with various linkages. Arzneimittelforschung Drug Research, 62(6), 261-266. 10.1055/s-0032-1306273 DOI: https://doi.org/10.1055/s-0032-1306273

Zhou, T., Hider, R. C., Jenner, P., Campbell, B., Hobbs, C. J., Rose, S., Jairaj, M., Tayarani-Binazir, K. A., & Syme, A. (2010). Design, synthesis and biological evaluation of L-dopa amide derivatives as potential prodrugs for the treatment of Parkinson’s disease. Eurpean Journal of Medicinal Chemistry, 45(9), 4035-4042. https://doi.org/10.1016/j.ejmech.2010.05.062 DOI: https://doi.org/10.1016/j.ejmech.2010.05.062

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Published

2023-10-01

How to Cite

Raju, R., Nayak, A., Das, P., Gajmer, A., A, R., & R, T. (2023). Advanced prodrug approaches for neurodegenerative diseases. Brazilian Journal of Science, 2(10), 1–12. https://doi.org/10.14295/bjs.v2i10.369