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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Review Article

Current Research on Pro-drug Therapies for Parkinson's and Alzheimer's Disease

Author(s): Cui Huo, Lei Wu, Zhiqiang Jiang, Jiacheng Yang, Zhouyu Wang, Yuzhi Li and Shan Qian*

Volume 18, Issue 6, 2022

Published on: 12 January, 2022

Page: [655 - 666] Pages: 12

DOI: 10.2174/1573406418666211130150821

Price: $65

Abstract

Background: Alzheimer's disease (AD) and Parkinson's (PD) disease are common neurodegenerative conditions of the Central Nervous System (CNS). Thus, these diseases have only been treated symptomatically since no approved drug is available that provides a complete cure.

Objectives: Through reading relevant literatures published at home and abroad, the method and significance of prodrug strategy to increase the efficacy of ad and pd drugs were discussed.

Methods: The biological mechanisms and currently approved drugs for both diseases have been discussed, revealing that most of these treatments utilized existing prodrug design strategies, including increased lipophilicity, and the use of transporters mediation and bio-oxidation to improve oral bioavailability and brain permeability.

Results: The purpose of this paper is to review the research progress in the treatment of Neurodegenerative Diseases (NDDS), especially ad and pd, using the prodrug strategy. The research of drug bioavailability and the prodrug strategy of cns targeted drug delivery lay the foundation for drug development to treat these diseases.

Conclusion: The use of prodrug strategies provides important opportunities for the development of novel therapies for ad and pd.

Keywords: Neurodegenerative diseases, prodrug strategies, oral bioavailability, the brain permeability, alzheimer's disease, parkinson's disease.

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[1]
Moreno-García, L.; López-Royo, T.; Calvo, A.C.; Toivonen, J.M.; de la Torre, M.; Moreno-Martínez, L.; Molina, N.; Aparicio, P.; Zaragoza, P.; Manzano, R.; Osta, R. competing endogenous RNA networks as biomarkers in neurodegenerative diseases. Int. J. Mol. Sci., 2020, 21(24)E9582
[http://dx.doi.org/10.3390/ijms21249582] [PMID: 33339180]
[2]
Neueder, A. RNA-mediated disease mechanisms in neurodegenerative disorders. J. Mol. Biol., 2019, 431(9), 1780-1791.
[http://dx.doi.org/10.1016/j.jmb.2018.12.012] [PMID: 30597161]
[3]
Gromadzka, G.; Tarnacka, B.; Flaga, A.; Adamczyk, A. Copper dyshomeostasis in neurodegenerative diseases-therapeutic implications. Int. J. Mol. Sci., 2020, 21(23), 35.
[http://dx.doi.org/10.3390/ijms21239259] [PMID: 33291628]
[4]
DiNunzio, J.C.; Williams, R.O. III CNS disorders-current treatment options and the prospects for advanced therapies. Drug Dev. Ind. Pharm., 2008, 34(11), 1141-1167.
[http://dx.doi.org/10.1080/03639040802020536] [PMID: 18720140]
[5]
Bhat, S.; Acharya, U.R.; Hagiwara, Y.; Dadmehr, N.; Adeli, H. Parkinson’s disease: Cause factors, measurable indicators, and early diagnosis. Comput. Biol. Med., 2018, 102, 234-241.
[http://dx.doi.org/10.1016/j.compbiomed.2018.09.008] [PMID: 30253869]
[6]
Scholefield, M.; Unwin, R.D.; Cooper, G.J.S. Shared perturbations in the metallome and metabolome of Alzheimer’s, Parkinson’s, Huntington’s, and dementia with Lewy bodies: A systematic review. Ageing Res. Rev., 2020, 63101152
[http://dx.doi.org/10.1016/j.arr.2020.101152] [PMID: 32846222]
[7]
Mansor, N.I.; Nordin, N.; Mohamed, F.; Ling, K.H.; Rosli, R.; Hassan, Z. Crossing the blood-brain barrier: A review on drug delivery strategies for treatment of the central nervous system diseases. Curr. Drug Deliv., 2019, 16(8), 698-711.
[http://dx.doi.org/10.2174/1567201816666190828153017] [PMID: 31456519]
[8]
Müller, C.E. Prodrug approaches for enhancing the bioavailability of drugs with low solubility. Chem. Biodivers., 2009, 6(11), 2071-2083.
[http://dx.doi.org/10.1002/cbdv.200900114] [PMID: 19937841]
[9]
Wang, T.; Liu, X.H.; Guan, J.; Ge, S.; Wu, M-B.; Lin, J.P.; Yang, L.R. Advancement of multi-target drug discoveries and promising applications in the field of Alzheimer’s disease. Eur. J. Med. Chem., 2019, 169, 200-223.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.076] [PMID: 30884327]
[10]
Guo, L.; Ren, J.; Jiang, X. Perspectives on brain-targeting drug delivery systems. Curr. Pharm. Biotechnol., 2012, 13(12), 2310-2318.
[http://dx.doi.org/10.2174/138920112803341770] [PMID: 23016637]
[11]
Stockwell, J.; Abdi, N.; Lu, X.; Maheshwari, O.; Taghibiglou, C. Novel central nervous system drug delivery systems. Chem. Biol. Drug Des., 2014, 83(5), 507-520.
[http://dx.doi.org/10.1111/cbdd.12268] [PMID: 24325540]
[12]
Sozio, P.; Cerasa, L.S.; Abbadessa, A.; Di Stefano, A. Designing prodrugs for the treatment of Parkinson’s disease. Expert Opin. Drug Discov., 2012, 7(5), 385-406.
[http://dx.doi.org/10.1517/17460441.2012.677025] [PMID: 22494466]
[13]
Dahan, A.; Zimmermann, E.M.; Ben-Shabat, S. Modern prodrug design for targeted oral drug delivery. Molecules, 2014, 19(10), 16489-16505.
[http://dx.doi.org/10.3390/molecules191016489] [PMID: 25317578]
[14]
Cummings, J.L.; Morstorf, T.; Zhong, K. Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures. Alzheimers Res. Ther., 2014, 6(4), 37.
[http://dx.doi.org/10.1186/alzrt269] [PMID: 25024750]
[15]
Devenish, S.R.A. The current landscape in Alzheimer’s disease research and drug discovery. Drug Discov. Today, 2020, 25(6), 943-945.
[http://dx.doi.org/10.1016/j.drudis.2020.04.002] [PMID: 32360713]
[16]
Kumar, A.; Singh, A. Ekavali, A review on Alzheimer’s disease pathophysiology and its management: An update. Pharmacol. Rep., 2015, 67(2), 195-203.
[http://dx.doi.org/10.1016/j.pharep.2014.09.004] [PMID: 25712639]
[17]
Viña, J.; Sanz-Ros, J. Alzheimer’s disease: Only prevention makes sense. Eur. J. Clin. Invest., 2018, 48(10)e13005
[http://dx.doi.org/10.1111/eci.13005] [PMID: 30028503]
[18]
Yan, W.; Wu, J.; Song, B.; Luo, Q.; Xu, Y. Treatment with a brain-selective prodrug of 17β-estradiol improves cognitive function in Alzheimer’s disease mice by regulating klf5-NF-κB pathway. Naunyn Schmiedebergs Arch. Pharmacol., 2019, 392(7), 879-886.
[http://dx.doi.org/10.1007/s00210-019-01639-w] [PMID: 30879099]
[19]
Pardridge, W.M. Treatment of Alzheimer’s Disease and Blood-Brain Barrier Drug Delivery. Pharmaceuticals (Basel), 2020, 13(11)E394
[http://dx.doi.org/10.3390/ph13110394] [PMID: 33207605]
[20]
Vytla, D.; Combs-Bachmann, R.E.; Hussey, A.M.; McCarron, S.T.; McCarthy, D.S.; Chambers, J.J. Prodrug approaches to reduce hyperexcitation in the CNS. Adv. Drug Deliv. Rev., 2012, 64(7), 666-685.
[http://dx.doi.org/10.1016/j.addr.2011.11.007] [PMID: 22138074]
[21]
Gunnar; K.; Gouras; Davide; Tampellini; Reisuke; H.; TakahashiEstibaliz; Capetillo-Zarate, Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol., 2010, 119(5), 523-541.
[22]
Bruni, A.C.; Bernardi, L.; Gabelli, C. From beta amyloid to altered proteostasis in Alzheimer’s disease. Ageing Res. Rev., 2020, 64101126
[http://dx.doi.org/10.1016/j.arr.2020.101126] [PMID: 32683041]
[23]
Birks, J.S.; Harvey, R.J. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst. Rev., 2018, 6(6)CD001190
[http://dx.doi.org/10.1002/14651858.CD001190.pub3]
[24]
Toublet, F-X.; Lecoutey, C.; Lalut, J.; Hatat, B.; Davis, A.; Since, M.; Corvaisier, S.; Freret, T.; Sopkova de Oliveira Santos, J.; Claeysen, S.; Boulouard, M.; Dallemagne, P.; Rochais, C. Inhibiting acetylcholinesterase to activate pleiotropic prodrugs with therapeutic interest in Alzheimer’s disease. Molecules, 2019, 24(15)E2786
[http://dx.doi.org/10.3390/molecules24152786] [PMID: 31370232]
[25]
Sahoo, A.K.; Dandapat, J.; Dash, U.C.; Kanhar, S. Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer’s disease. J. Ethnopharmacol., 2018, 215, 42-73.
[http://dx.doi.org/10.1016/j.jep.2017.12.015] [PMID: 29248451]
[26]
Ng, Y.P.; Or, T.C.T.; Ip, N.Y. Plant alkaloids as drug leads for Alzheimer’s disease. Neurochem. Int., 2015, 89, 260-270.
[http://dx.doi.org/10.1016/j.neuint.2015.07.018] [PMID: 26220901]
[27]
Girek, M.; Szymanski, P. Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: Influence of chemical structures on biological activities. Chem. Pap., 2019, 73(2), 269-289.
[http://dx.doi.org/10.1007/s11696-018-0590-8]
[28]
Howard, R.; McShane, R.; Lindesay, J.; Ritchie, C.; Baldwin, A.; Barber, R.; Burns, A.; Dening, T.; Findlay, D.; Holmes, C.; Hughes, A.; Jacoby, R.; Jones, R.; Jones, R.; McKeith, I.; Macharouthu, A.; O’Brien, J.; Passmore, P.; Sheehan, B.; Juszczak, E.; Katona, C.; Hills, R.; Knapp, M.; Ballard, C.; Brown, R.; Banerjee, S.; Onions, C.; Griffin, M.; Adams, J.; Gray, R.; Johnson, T.; Bentham, P.; Phillips, P. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N. Engl. J. Med., 2012, 366(10), 893-903.
[http://dx.doi.org/10.1056/NEJMoa1106668] [PMID: 22397651]
[29]
Reddy, P.H. Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med., 2008, 10(4), 291-315.
[http://dx.doi.org/10.1007/s12017-008-8044-z] [PMID: 18566920]
[30]
Alley, G.M.; Bailey, J.A.; Chen, D.; Ray, B.; Puli, L.K.; Tanila, H.; Banerjee, P.K.; Lahiri, D.K. Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP/PS1 transgenic mice. J. Neurosci. Res., 2010, 88(1), 143-154.
[http://dx.doi.org/10.1002/jnr.22172] [PMID: 19642202]
[31]
Shastry, B.S. Parkinson disease: Etiology, pathogenesis and future of gene therapy. Neurosci. Res., 2001, 41(1), 5-12.
[http://dx.doi.org/10.1016/S0168-0102(01)00254-1] [PMID: 11535288]
[32]
Lotharius, J.; Brundin, P. Pathogenesis of Parkinson’s disease: Dopamine, vesicles and alpha-synuclein. Nat. Rev. Neurosci., 2002, 3(12), 932-942.
[http://dx.doi.org/10.1038/nrn983] [PMID: 12461550]
[33]
Senek, M.; Nyholm, D. Continuous drug delivery in Parkinson’s disease. CNS Drugs, 2014, 28(1), 19-27.
[http://dx.doi.org/10.1007/s40263-013-0127-1] [PMID: 24323838]
[34]
Haddad, F.; Sawalha, M.; Khawaja, Y.; Najjar, A.; Karaman, R. Dopamine and levodopa prodrugs for the treatment of Parkinson’s disease. Molecules, 2017, 23(1)E40
[http://dx.doi.org/10.3390/molecules23010040] [PMID: 29295587]
[35]
Urso, D.; Chaudhuri, K.R.; Qamar, M.A.; Jenner, P. Improving the delivery of levodopa in Parkinson’s disease: A review of approved and emerging therapies. CNS Drugs, 2020, 34(11), 1149-1163.
[http://dx.doi.org/10.1007/s40263-020-00769-7] [PMID: 33146817]
[36]
Di Stefano, A.; Sozio, P.; Cerasa, L.S.; Iannitelli, A. L-Dopa prodrugs: An overview of trends for improving Parkinson’s disease treatment. Curr. Pharm. Des., 2011, 17(32), 3482-3493.
[http://dx.doi.org/10.2174/138161211798194495] [PMID: 22074421]
[37]
Cacciatore, I.; Ciulla, M.; Marinelli, L.; Eusepi, P.; Di Stefano, A. Advances in prodrug design for Parkinson’s disease. Expert Opin. Drug Discov., 2018, 13(4), 295-305.
[http://dx.doi.org/10.1080/17460441.2018.1429400] [PMID: 29361853]
[38]
Karaman, R. Prodrugs-current and future drug development strategy. Int. J. Med. Pharm. Case Reports, 2014, 1(2), 58-63.
[http://dx.doi.org/10.9734/IJMPCR/2014/13183]
[39]
Di Stefano, A.; Carafa, M.; Sozio, P.; Pinnen, F.; Braghiroli, D.; Orlando, G.; Cannazza, G.; Ricciutelli, M.; Marianecci, C.; Santucci, E. Evaluation of rat striatal L-dopa and DA concentration after intraperitoneal administration of L-dopa prodrugs in liposomal formulations. J. Control. Release, 2004, 99(2), 293-300.
[http://dx.doi.org/10.1016/j.jconrel.2004.07.010] [PMID: 15380638]
[40]
Jimenez-Shahed, J. A review of current and novel levodopa formulations for the treatment of Parkinson’s disease. Ther. Deliv., 2016, 7(3), 179-191.
[http://dx.doi.org/10.4155/tde.15.96] [PMID: 26893250]
[41]
Giorgioni, G.; Claudi, F.; Ruggieri, S.; Ricciutelli, M.; Palmieri, G.F.; Di Stefano, A.; Sozio, P.; Cerasa, L.S.; Chiavaroli, A.; Ferrante, C.; Orlando, G.; Glennon, R.A. Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs. Bioorg. Med. Chem., 2010, 18(5), 1834-1843.
[http://dx.doi.org/10.1016/j.bmc.2010.01.041] [PMID: 20153654]
[42]
Hoon, M.; Petzer, J.P.; Viljoen, F.; Petzer, A. The design and evaluation of an l-dopa-lazabemide prodrug for the treatment of Parkinson’s disease. Molecules, 2017, 22(12)E2076
[http://dx.doi.org/10.3390/molecules22122076] [PMID: 29186917]
[43]
Zhou, T.; Hider, R.C.; Jenner, P.; Campbell, B.; Hobbs, C.J.; Rose, S.; Jairaj, M.; Tayarani-Binazir, K.A.; Syme, A. Design, synthesis and biological evaluation of L-dopa amide derivatives as potential prodrugs for the treatment of Parkinson’s disease. Eur. J. Med. Chem., 2010, 45(9), 4035-4042.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.062] [PMID: 20646792]
[44]
Shi, S.; Wang, Z.; Qiao, Z. The multifunctional anti-inflammatory drugs used in the therapy of Alzheimer’s disease. Curr. Med. Chem., 2013, 20(20), 2583-2588.
[http://dx.doi.org/10.2174/0929867311320200006] [PMID: 23590711]
[45]
LeWitt, P.A.; Huff, F.J.; Hauser, R.A.; Chen, D.; Lissin, D.; Zomorodi, K.; Cundy, K.C. Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson’s disease. Mov. Disord., 2014, 29(1), 75-82.
[http://dx.doi.org/10.1002/mds.25742] [PMID: 24339234]
[46]
Scaturro, A.L.; De Caro, V.; Campisi, G.; Giannola, L.I. Potential transbuccal delivery of l-DOPA methylester prodrug: Stability in the environment of the oral cavity and ability to cross the mucosal tissue. Drug Deliv., 2016, 23(7), 2355-2362.
[http://dx.doi.org/10.3109/10717544.2014.987332] [PMID: 25533875]
[47]
Olatunji, F.P.; Kesic, B.N.; Choy, C.J.; Berkman, C.E. Phosphoramidate derivates as controlled-release prodrugs of l-Dopa. Bioorg. Med. Chem. Lett., 2019, 29(18), 2571-2574.
[http://dx.doi.org/10.1016/j.bmcl.2019.08.005] [PMID: 31400939]
[48]
Zwilling, D.; Huang, S-Y.; Sathyasaikumar, K.V.; Notarangelo, F.M.; Guidetti, P.; Wu, H-Q.; Lee, J.; Truong, J.; Andrews-Zwilling, Y.; Hsieh, E.W.; Louie, J.Y.; Wu, T.; Scearce-Levie, K.; Patrick, C.; Adame, A.; Giorgini, F.; Moussaoui, S.; Laue, G.; Rassoulpour, A.; Flik, G.; Huang, Y.; Muchowski, J.M.; Masliah, E.; Schwarcz, R.; Muchowski, P.J. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 2011, 145(6), 863-874.
[http://dx.doi.org/10.1016/j.cell.2011.05.020] [PMID: 21640374]
[49]
Saydoff, J.A.; Olariu, A.; Sheng, J.; Hu, Z.; Li, Q.; Garcia, R.; Pei, J.; Sun, G.Y.; von Borstel, R. Uridine prodrug improves memory in Tg2576 and TAPP mice and reduces pathological factors associated with Alzheimer’s disease in related models. J. Alzheimers Dis., 2013, 36(4), 637-657.
[http://dx.doi.org/10.3233/JAD-130059] [PMID: 23648515]
[50]
Borkar, N.; Li, B.; Holm, R.; Håkansson, A.E.; Müllertz, A.; Yang, M.; Mu, H. Lipophilic prodrugs of apomorphine I: Preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media. Eur. J. Pharm. Biopharm., 2015, 89, 216-223.
[http://dx.doi.org/10.1016/j.ejpb.2014.12.014] [PMID: 25513957]
[51]
Hey, J.A.; Yu, J.Y.; Versavel, M.; Abushakra, S.; Kocis, P.; Power, A.; Kaplan, P.L.; Amedio, J.; Tolar, M. Clinical pharmacokinetics and safety of ALZ-801, a Novel Prodrug of Tramiprosate in development for the treatment of Alzheimer’s disease. Clin. Pharmacokinet., 2018, 57(3), 315-333.
[http://dx.doi.org/10.1007/s40262-017-0608-3] [PMID: 29063518]
[52]
Tolar, M.; Abushakra, S.; Hey, J.A.; Porsteinsson, A.; Sabbagh, M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res. Ther., 2020, 12(1), 95.
[http://dx.doi.org/10.1186/s13195-020-00663-w] [PMID: 32787971]
[53]
Chen, C.; Wang, Z.; Zhang, Z.; Liu, X.; Kang, S.S.; Zhang, Y.; Ye, K. The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2018, 115(3), 578-583.
[http://dx.doi.org/10.1073/pnas.1718683115] [PMID: 29295929]
[54]
Wang, J.; Tan, L.; Wang, H-F.; Tan, C-C.; Meng, X-F.; Wang, C.; Tang, S-W.; Yu, J-T. Anti-inflammatory drugs and risk of Alzheimer’s disease: An updated systematic review and meta-analysis. J. Alzheimers Dis., 2015, 44(2), 385-396.
[http://dx.doi.org/10.3233/JAD-141506] [PMID: 25227314]
[55]
Dvir, E.; Elman, A.; Simmons, D.; Shapiro, I.; Duvdevani, R.; Dahan, A.; Hoffman, A.; Friedman, J.E. DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and Alzheimer’s disease therapy. CNS Drug Rev., 2007, 13(2), 260-277.
[http://dx.doi.org/10.1111/j.1527-3458.2007.00014.x] [PMID: 17627676]
[56]
Pignatello, R.; Pantò, V.; Salmaso, S.; Bersani, S.; Pistarà, V.; Kepe, V.; Barrio, J.R.; Puglisi, G. Flurbiprofen derivatives in Alzheimer’s disease: Synthesis, pharmacokinetic and biological assessment of lipoamino acid prodrugs. Bioconjug. Chem., 2008, 19(1), 349-357.
[http://dx.doi.org/10.1021/bc700312y] [PMID: 18072715]
[57]
Sheha, M. Pharmacokinetic and ulcerogenic studies of naproxen prodrugs designed for specific brain delivery. Arch. Pharm. Res., 2012, 35(3), 523-530.
[http://dx.doi.org/10.1007/s12272-012-0316-3] [PMID: 22477200]
[58]
Wang, L.; Zhang, L.; Zhao, Y.; Fu, Q.; Xiao, W.; Lu, R.; Hai, L.; Guo, L.; Wu, Y. Design, synthesis, and neuroprotective effects of dual-brain targeting naproxen prodrug. Arch. Pharm. (Weinheim), 2018, 351(5)e1700382
[http://dx.doi.org/10.1002/ardp.201700382] [PMID: 29566434]
[59]
Chen, Q.; Gong, T.; Liu, J.; Wang, X.; Fu, H.; Zhang, Z. Synthesis, in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery. J. Drug Target., 2009, 17(4), 318-328.
[http://dx.doi.org/10.1080/10611860902795399] [PMID: 19558357]
[60]
Oldendorf, W.H. Lipid solubility and drug penetration of the blood brain barrier. Proc. Soc. Exp. Biol. Med., 1974, 147(3), 813-815.
[http://dx.doi.org/10.3181/00379727-147-38444] [PMID: 4445171]
[61]
Oliver, D.M.A.; Reddy, P.H. Small molecules as therapeutic drugs for Alzheimer’s disease. Mol. Cell. Neurosci., 2019, 96, 47-62.
[http://dx.doi.org/10.1016/j.mcn.2019.03.001] [PMID: 30877034]
[62]
Anderson, B.D. Prodrugs for improved CNS delivery. Adv. Drug Deliv. Rev., 1996, 19(2), 171-202.
[http://dx.doi.org/10.1016/0169-409X(95)00106-H]
[63]
Deguchi, Y.; Hayashi, H.; Fujii, S.; Naito, T.; Yokoyama, Y.; Yamada, S.; Kimura, R. 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. J. Drug Target., 2000, 8(6), 371-381.
[http://dx.doi.org/10.3109/10611860008997913] [PMID: 11328663]
[64]
Pavan, B.; Dalpiaz, A.; Ciliberti, N.; Biondi, C.; Manfredini, S.; Vertuani, S. Progress in drug delivery to the central nervous system by the prodrug approach. Molecules, 2008, 13(5), 1035-1065.
[http://dx.doi.org/10.3390/molecules13051035] [PMID: 18560328]
[65]
Baakman, A.C.; ’t Hart, E.; Kay, D.G.; Stevens, J.; Klaassen, E.S.; Maelicke, A.; Groeneveld, G.J. First in human study with a prodrug of galantamine: Improved benefit-risk ratio? Alzheimers Dement. (N. Y.), 2016, 2(1), 13-22.
[http://dx.doi.org/10.1016/j.trci.2015.12.003] [PMID: 29067291]
[66]
Bakker, C.; van der Aart, J.; Hart, E.P.; Klaassen, E.S.; Bergmann, K.R.; van Esdonk, M.J.; Kay, D.G.; Groeneveld, G.J. Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine. Alzheimers Dement. (N. Y.), 2020, 6(1), e12093-e12093.
[http://dx.doi.org/10.1002/trc2.12093] [PMID: 33083515]
[67]
Ferrara, S.J.; Scanlan, T.S. A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators. J. Med. Chem., 2020, 63(17), 9742-9751.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00868] [PMID: 32787092]
[68]
Kishimoto, Y.; Johnson, J.; Fang, W.; Halpern, J.; Marosi, K.; Liu, D.; Geisler, J.G.; Mattson, M.P. A mitochondrial uncoupler prodrug protects dopaminergic neurons and improves functional outcome in a mouse model of Parkinson’s disease. Neurobiol. Aging, 2020, 85, 123-130.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.09.011] [PMID: 31718928]
[69]
Peura, L.; Malmioja, K.; Laine, K.; Leppänen, J.; Gynther, M.; Isotalo, A.; Rautio, J. Large amino acid transporter 1 (LAT1) prodrugs of valproic acid: New prodrug design ideas for central nervous system delivery. Mol. Pharm., 2011, 8(5), 1857-1866.
[http://dx.doi.org/10.1021/mp2001878] [PMID: 21770378]
[70]
Ylikangas, H.; Peura, L.; Malmioja, K.; Leppänen, J.; Laine, K.; Poso, A.; Lahtela-Kakkonen, M.; Rautio, J. Structure-activity relationship study of compounds binding to large amino acid transporter 1 (LAT1) based on pharmacophore modeling and in situ rat brain perfusion. Eur. J. Pharm. Sci., 2013, 48(3), 523-531.
[http://dx.doi.org/10.1016/j.ejps.2012.11.014] [PMID: 23228412]
[71]
Rautio, J.; Laine, K.; Gynther, M.; Savolainen, J. Prodrug approaches for CNS delivery. AAPS J., 2008, 10(1), 92-102.
[http://dx.doi.org/10.1208/s12248-008-9009-8] [PMID: 18446509]
[72]
Peura, L.; Malmioja, K.; Huttunen, K.; Leppänen, J.; Hämäläinen, M.; Forsberg, M.M.; Gynther, M.; Rautio, J.; Laine, K. Design, synthesis and brain uptake of LAT1-targeted amino acid prodrugs of dopamine. Pharm. Res., 2013, 30(10), 2523-2537.
[http://dx.doi.org/10.1007/s11095-012-0966-3] [PMID: 24137801]
[73]
Puris, E.; Gynther, M.; Huttunen, J.; Auriola, S.; Huttunen, K.M. L-type amino acid transporter 1 utilizing prodrugs of ferulic acid revealed structural features supporting the design of prodrugs for brain delivery. Eur. J. Pharm. Sci., 2019, 129, 99-109.
[http://dx.doi.org/10.1016/j.ejps.2019.01.002] [PMID: 30625368]
[74]
Huttunen, J.; Peltokangas, S.; Gynther, M.; Natunen, T.; Hiltunen, M.; Auriola, S.; Ruponen, M.; Vellonen, K-S.; Huttunen, K.M. L-Type Amino Acid Transporter 1 (LAT1/Lat1)-utilizing prodrugs can improve the delivery of drugs into neurons, astrocytes and microglia. Sci. Rep., 2019, 9(1), 12860.
[http://dx.doi.org/10.1038/s41598-019-49009-z] [PMID: 31492955]
[75]
Tampio, J.; Huttunen, J.; Montaser, A.; Huttunen, K.M. Targeting of perforin inhibitor into the brain parenchyma via a prodrug approach can decrease oxidative stress and neuroinflammation and improve cell survival. Mol. Neurobiol., 2020, 57(11), 4563-4577.
[http://dx.doi.org/10.1007/s12035-020-02045-7] [PMID: 32754897]
[76]
Gynther, M.; Ropponen, J.; Laine, K.; Leppänen, J.; Haapakoski, P.; Peura, L.; Järvinen, T.; Rautio, J. Glucose promoiety enables glucose transporter mediated brain uptake of ketoprofen and indomethacin prodrugs in rats. J. Med. Chem., 2009, 52(10), 3348-3353.
[http://dx.doi.org/10.1021/jm8015409] [PMID: 19402664]
[77]
Qiu, S.B.; Zhao, Y.; Liu, S.; Li, X.C.; Guo, L.; Hai, L.; Wu, Y. Design, synthesis and evaluation of dual-targeting prodrug co-modified by organic amine and l-ascorbic acid for CNS delivery. Lett. Drug Des. Discov., 2017, 14(9), 1065-1072.
[http://dx.doi.org/10.2174/1570180814666161230161152]
[78]
Zhao, Y.; Zhang, L.; Peng, Y.; Yue, Q.; Hai, L.; Guo, L.; Wang, Q.; Wu, Y. GLUT1 -mediated venlafaxine-thiamine disulfide system-glucose conjugates with “lock-in” function for central nervous system delivery. Chem. Biol. Drug Des., 2018, 91(3), 707-716.
[http://dx.doi.org/10.1111/cbdd.13128] [PMID: 29063718]
[79]
Gündüz, Ş.; Kandeğer, A.; Selvi, Y. Comparison of venlafaxine alone versus venlafaxine plus late partial sleep deprivation therapy combination for major depressive disorder. Chronobiol. Int., 2021, 38(3), 378-386.
[http://dx.doi.org/10.1080/07420528.2020.1842753] [PMID: 33317355]
[80]
Scott, L.E.; Page, B.D.G.; Patrick, B.O.; Orvig, C. Altering pyridinone N-substituents to optimise activity as potential prodrugs for Alzheimer’s disease. Dalton Trans., 2008, (45), 6364-6367.
[http://dx.doi.org/10.1039/b815404j] [PMID: 19002321]
[81]
Dholkawala, F.; Voshavar, C.; Dutta, A.K. Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson’s disease. Eur. J. Pharm. Biopharm., 2016, 103, 62-70.
[http://dx.doi.org/10.1016/j.ejpb.2016.03.017] [PMID: 26994936]
[82]
Park, T.E.; Singh, B.; Li, H.; Lee, J.Y.; Kang, S.K.; Choi, Y.J.; Cho, C.S. Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer’s disease. Biomaterials, 2015, 38, 61-71.
[http://dx.doi.org/10.1016/j.biomaterials.2014.10.068] [PMID: 25457984]
[83]
Peauger, L.; Azzouz, R.; Gembus, V.; Ţînţaş, M-L.; Sopková-de Oliveira Santos, J.; Bohn, P.; Papamicaël, C.; Levacher, V. Donepezil-based central acetylcholinesterase inhibitors by means of a “bio-oxidizable” prodrug strategy: Design, synthesis, and in vitro biological evaluation. J. Med. Chem., 2017, 60(13), 5909-5926.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00702] [PMID: 28613859]
[84]
Alix, F.; Gembus, V.; Coquet, L.; Hubert-Roux, M.; Chan, P.; Truong, L.; Sebban, M.; Coadou, G.; Oulyadi, H.; Papamicael, C.; Levacher, V. Dihydroquinoline carbamate DQS1-02 as a prodrug of a potent acetylcholinesterase inhibitor for Alzheimer’s disease therapy: Multigram-scale synthesis, mechanism investigations, in vitro safety pharmacology, and preliminary in vivo toxicology profile. ACS Omega, 2018, 3(12), 18387-18397.
[http://dx.doi.org/10.1021/acsomega.8b02121]
[85]
Ţînţaş, M-L.; Azzouz, R.; Peauger, L.; Gembus, V.; Petit, E.; Bailly, L.; Papamicaël, C.; Levacher, V. Access to highly enantioenriched donepezil-like 1,4-dihydropyridines as promising anti-Alzheimer prodrug candidates via enantioselective Tsuji allylation and organocatalytic aza-ene-type domino reactions. J. Org. Chem., 2018, 83(17), 10231-10240.
[http://dx.doi.org/10.1021/acs.joc.8b01442] [PMID: 30004228]
[86]
Barré, A.; Azzouz, R.; Gembus, V.; Papamicaël, C.; Levacher, V. Design, synthesis, and in vitro biological activities of a bio-oxidizable prodrug to deliver both ChEs and DYRK1A inhibitors for AD therapy. Molecules, 2019, 24(7)E1264
[http://dx.doi.org/10.3390/molecules24071264] [PMID: 30939771]
[87]
Bimonte-Nelson, H.A.; Acosta, J.I.; Talboom, J.S. Neuroscientists as cartographers: Mapping the crossroads of gonadal hormones, memory and age using animal models. Molecules, 2010, 15(9), 6050-6105.
[http://dx.doi.org/10.3390/molecules15096050] [PMID: 20877209]
[88]
Li, R.; Cui, J.; Shen, Y. Brain sex matters: estrogen in cognition and Alzheimer’s disease. Mol. Cell. Endocrinol., 2014, 389(1-2), 13-21.
[http://dx.doi.org/10.1016/j.mce.2013.12.018] [PMID: 24418360]
[89]
Prokai-Tatrai, K.; Nguyen, V.; Prokai, L. 10β,17α-Dihydroxyestra-1,4-dien-3-one: A 10β,17α-Dihydroxyestra-1,4-dien-3-one: A bioprecursor prodrug preferentially producing 17α-estradiol in the brain for targeted neurotherapy. ACS Chem. Neurosci., 2018, 9(11), 2528-2533.
[http://dx.doi.org/10.1021/acschemneuro.8b00184] [PMID: 29843514]
[90]
Kim, G.H.; Kim, J.E.; Rhie, S.J.; Yoon, S. The role of oxidative stress in neurodegenerative diseases. Exp. Neurobiol., 2015, 24(4), 325-340.
[http://dx.doi.org/10.5607/en.2015.24.4.325] [PMID: 26713080]
[91]
Wang, X.; Wang, W.; Li, L.; Perry, G.; Lee, H.G.; Zhu, X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim. Biophys. Acta, 2014, 1842(8), 1240-1247.
[http://dx.doi.org/10.1016/j.bbadis.2013.10.015] [PMID: 24189435]
[92]
Yan, K-C.; Sedgwick, A.C.; Zang, Y.; Chen, G-R.; He, X-P.; Li, J.; Yoon, J.; James, T.D. Sensors, imaging agents, and theranostics to help understand and treat reactive oxygen species related diseases. Small Methods, 2019, 3(7)
[http://dx.doi.org/10.1002/smtd.201900013]
[93]
Morrison, L.D.; Smith, D.D.; Kish, S.J. Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J. Neurochem., 1996, 67(3), 1328-1331.
[http://dx.doi.org/10.1046/j.1471-4159.1996.67031328.x] [PMID: 8752143]
[94]
Sestito, S.; Daniele, S.; Pietrobono, D.; Citi, V.; Bellusci, L.; Chiellini, G.; Calderone, V.; Martini, C.; Rapposelli, S. Memantine prodrug as a new agent for Alzheimer’s Disease. Sci. Rep., 2019, 9(1), 4612.
[http://dx.doi.org/10.1038/s41598-019-40925-8] [PMID: 30874573]
[95]
Oliveri, V.; Vecchio, G. Prochelator strategies for site-selective activation of metal chelators. J. Inorg. Biochem., 2016, 162, 31-43.
[http://dx.doi.org/10.1016/j.jinorgbio.2016.05.012] [PMID: 27297691]
[96]
Jia, J.Y.; Zhao, Q.H.; Liu, Y.; Gui, Y.Z.; Liu, G.Y.; Zhu, D.Y.; Yu, C.; Hong, Z. Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer’s disease. Acta Pharmacol. Sin., 2013, 34(7), 976-982.
[http://dx.doi.org/10.1038/aps.2013.7] [PMID: 23624756]
[97]
Liang, Y.Q.; Tang, X.C. Comparative effects of huperzine A, donepezil and rivastigmine on cortical acetylcholine level and acetylcholinesterase activity in rats. Neurosci. Lett., 2004, 361(1-3), 56-59.
[http://dx.doi.org/10.1016/j.neulet.2003.12.071] [PMID: 15135892]

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