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Review

Advances in prodrug design for Alzheimer’s disease: the state of the art

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 325-341 | Received 05 Nov 2021, Accepted 17 Jan 2022, Published online: 23 Feb 2022

References

  • Patterson C. No title. World Alzheimer Rep. London: ADI; 2018.
  • Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–185.
  • Cummings J, Lee G, and Ritter A, et al. Alzheimer’s Disease drug development pipeline: 2019. Alzheimer’s Dement Transl Res Clin Interv. 2019;5(1):272–293. DOI:https://doi.org/10.1016/j.trci.2019.05.008.
  • Zemek F, Drtinova L, Nepovimova E, et al. Outcomes of Alzheimer’s Disease Therapy with Acetylcholinesterase Inhibitors and Memantine. Expert Opin Drug Saf. 2014;13(6):759–774.
  • Sevigny J, Chiao P, Bussière T, et al. The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer’s Disease. Nature. 2016;537(7618):50–56.
  • Xia X, Zhou Y, Gao H. Prodrug Strategy for Enhanced Therapy of Central Nervous System Disease. Chem Commun. 2021;57(71):8842–8855.
  • Rautio J, Laine K, Gynther M, et al. Prodrug Approaches for CNS Delivery. AAPS J. 2008;10(1):92–102.
  • Patel MM, Goyal BR, Bhadada SV, et al. Getting into the Brain. CNS Drugs. 2009;23(1):35–58.
  • Iqbal K, and Grundke‐Iqbal I. Alzheimer’s disease, a multifactorial disorder seeking multitherapies. Alzheimer’s Dement. 2010;6(5):420–424. DOI:https://doi.org/10.1016/j.jalz.2010.04.006.
  • Frautschy SA, Cole GM. Why pleiotropic interventions are needed for Alzheimer’s Disease. Mol Neurobiol. 2010;41(2–3):392–409.
  • Fessel J. Alzheimer’s disease combination treatment. Neurobiol Aging. 2018;63:165.
  • Lalut J, Rochais C, Dallemagne P. Multiple ligands in neurodegenerative diseases. Drug Selectivity: An Evolving Concept in Medicinal Chemistry. 2017. Doi:https://doi.org/10.1002/9783527674381.ch16.
  • Rhea EM, and Banks WA. Role of the blood-brain barrier in central nervous system insulin resistance. Front Neurosci. 2019;13. DOI:https://doi.org/10.3389/fnins.2019.00521.
  • Bellettato CM, and Scarpa M. Possible strategies to cross the blood–brain barrier. Ital JPediatr. 2018;44(S2):131. DOI:https://doi.org/10.1186/s13052-018-0563-0.
  • Kell DB. Hitchhiking into the cell. Nat Chem Biol. 2020;16(4):367–368.
  • Mayol-Llinàs J, Nelson A, Farnaby W, et al. Assessing molecular scaffolds for CNS drug discovery. Drug Discov Today. 2017;22(7):965–969.
  • Wager TT, Hou X, Verhoest PR, et al. Central nervous system multiparameter optimization desirability: application in drug discovery. ACS Chem Neurosci. 2016;7(6):767–775.
  • Kharkar PS. Drugs acting on Central Nervous System (CNS) targets as leads for non-CNS targets. F1000Res. 2014;3:40.
  • Hu Y, Hammarlund-Udenaes M. Perspectives on nanodelivery to the brain: prerequisites for successful brain treatment. Mol Pharm. 2020;17(11):4029–4039.
  • Bodor N, Brewster ME. Problems of delivery of drugs to the brain. Pharmacol Ther. 1982;19(3):337–386.
  • Bodor N, Farag HH. Improved delivery through biological membranes. 11. A redox chemical drug-delivery system and its use for brain-specific delivery of phenylethylamine. J Med Chem. 1983;26(3):313–318.
  • Bodor N. Redox drug delivery systems for targeting drugs to the brain. Ann N Y Acad Sci. 1987;507(1 Biological Ap):289–306.
  • Scott LE, Page BDG, and Patrick BO, et al. Altering pyridinone N-substituents to optimise activity as potential prodrugs for Alzheimer’s disease. Dalt Trans. 2008;45:6364. DOI:https://doi.org/10.1039/b815404j.
  • Alix F, Gembus V, Coquet L, et al. 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.
  • Azzouz R, Peauger L, Gembus V, et al. Novel donepezil-like n -benzylpyridinium salt derivatives as ache inhibitors and their corresponding dihydropyridine “bio-oxidizable” prodrugs: synthesis, biological evaluation and structure-activity relationship. Eur J Med Chem. 2018;145:165–190.
  • Peauger L, Azzouz R, Gembus V, et al. 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.
  • Bohn P, Gourand F, Papamicaël C, et al. Dihydroquinoline carbamate derivatives as “Bio-oxidizable” prodrugs for brain delivery of acetylcholinesterase inhibitors: [11 C] radiosynthesis and biological evaluation. ACS Chem Neurosci. 2015;6(5):737–744.
  • Barré A, Azzouz R, Gembus V, et al. 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):1264.
  • Ţînţaş M-L, Azzouz R, Peauger L, et al. 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.
  • Tschiffely AE, Schuh RA, and Prokai-Tatrai K, et al. A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer’s disease. Horm Behav. 2016;83:39–44. https://doi.org/10.1016/j.yhbeh.2016.05.009.
  • Tschiffely AE, Schuh RA, and Prokai-Tatrai K, et al. An Exploratory Investigation of Brain-Selective Estrogen Treatment in Males Using a Mouse Model of Alzheimer’s Disease. Horm Behav. 2018;98:16–21. https://doi.org/10.1016/j.yhbeh.2017.11.015.
  • Kim M, Park MH, Nam G, et al. A glycosylated prodrug to attenuate neuroinflammation and improve cognitive deficits in Alzheimer’s disease transgenic mice. Mol Pharm. 2021;18(1):101–112.
  • García-Viñuales S, Ahmed R, Sciacca MFM, et al. Trehalose conjugates of silybin as prodrugs for targeting toxic Aβ aggregates. ACS Chem Neurosci. 2020;11(17):2566–2576.
  • Saydoff JA, Olariu A, Sheng J, et al. Uridine prodrug improves memory in Tg2576 and TAPP mice and reduces pathological factors associated with Alzheimer’s disease in related models. J Alzheimer’s Dis. 2013;36(4):637–657.
  • Gjervig JK, Kvaerno L, Jorgensen M, et al., Catecholamine prodrugs for use in the treatment of Parkinson’s disease. US2019160083. 2018 November 23.
  • Craig RA, Estrada AA, and Feng JA, et al. Denali therapeutics INC, compounds, compositions and methods. WO2019046779 (A1). 2019 March 07.
  • Byeon SR, Oh -S-S, and Kwon AR, et al. Kainos medicine inc. C-Nucleosides, C-Nucleotides and their analogs, equivalents and prodrugs thereof for ectonucleotidase inhibition. WO2021040356 (A1). 2021 March 04.
  • Deng H, Luo U, and Yusheng C, et al. Univ Beijing. Senolytic prodrugs and methods of use thereof. WO2021056270 (A1). 2021 April 01.
  • Jia J, Zhao Q, Liu Y, et al. 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.
  • Liu X, Qi Q, Xiao G, et al. O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB Receptor and Displays Antidepressant Activity. Pharmacology. 2013;91(3–4):185–200.
  • Tampio J, Huttunen J, Montaser A, et al. 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.
  • Sinha A, Chang JC, Xu P, et al. brain permeable tafamidis amide analogs for stabilizing TTR and reducing APP cleavage. ACS Med Chem Lett. 2020;11(10):1973–1979.
  • Min S-W, Chen X, Tracy TE, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21(10):1154–1162.
  • Pignatello R, Pantò V, Salmaso S, et al. Flurbiprofen derivatives in Alzheimer’s disease: synthesis, pharmacokinetic and biological assessment of Lipoamino Acid Prodrugs. Bioconjug Chem. 2008;19(1):349–357.
  • Cairns AG, Vazquez-Romero A, Mahdi Moein M, et al. Increased brain exposure of an alpha-synuclein fibrillization modulator by utilization of an activated ester prodrug strategy. ACS Chem Neurosci. 2018;9(11):2542–2547.
  • Baxter AD, and Walmsley A. Arakis LTD. Ifenprodil derivatives. GB2428675 (A). 2007 February 07.
  • Grass IGM. Neurovia INC. methods and compositions for treating demyelinating diseases using sobetirome or a sobetirome prodrug and a PPAR activator. US2018353450 (A1). 2018 December 13.
  • Denis A, Mirguet O, and Toum J. Glaxosmithkline LTD. Prodrug of 1,1’-(1,6-Dioxo-1,6-Hexanediyl)Bis-D-Proline. US2016081983 (A1). 2016 March 24.
  • Fan P, Lui RM, and Singh R, et al. Chemocentryx INC. Prodrugs of fused-bicyclic C5aR antagonists. US2019300526 (A1). 2019 October 03.
  • Tavares XF, and Vitek M. Resilio therapeutics LLC. Compounds for treatment of neurodegenerative diseases. WO2018085263 (A1). 2018 May 11.
  • Goel OP. SSV therapeutics. carnitine conjugates of adamantanamines and neramexane derivatives as dual prodrugs for various uses. US2009246267 (A1). 2009 October 01.
  • Coric V, Berman R, and Qureshi I. Biohaven therapeutics LTD. use of riluzole prodrugs to treat Alzheimer’s disease. WO2020023324 (A1). 2020 January 30.
  • Abushakra S, Power A, and Tolar M, et al. Alzheon INC. methods of treating neurodegenerative disordes in a particular patient population. WO2017044840 (A1). 2017 March 16.
  • Laufer R, and Ott GR. Cephalon INC. Prodrugs of Chlorokynurenines. WO2017044516 (A1). 2017 March 16.
  • Tauriello D, Byrom D, and Matarin Morales JA, et al. Univ Barcelona. TGFβ inhibitor and prodrugs. WO2020104648 (A2). 2020 May 28.
  • Wescott C, Hepner A, and Larson A. Eagle pharmaceuticals INC. dantrolene prodrugs and methods of their use. WO2019079721 (A1). 2019 March 25.
  • Slusher B, Rais R, and Vavra J, et al. Univ Johns Hopkins. Prodrugs of hydroxamate-based GCPII inhibitors. WO2018094334 (A1). 2018 May 24.
  • Savory E, Pritchard M, and Higginbottom M, et al. Proximagen LTD. Tonabersat prodrugs. WO2015097463 (A1). 2015 July 02.
  • Hey JA, Yu JY, Versavel M, et al. 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.
  • Hey JA, Kocis P, Hort J, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs. 2018;32(9):849–861.
  • Maelicke A, Hoeffle-Maas A, Ludwig J, et al. Memogain is a galantamine pro-drug having dramatically reduced adverse effects and enhanced efficacy. J Mol Neurosci. 2010;40(1–2):135–137.
  • Baakman AC, ’t Hart E, and Kay DG, et al. First in human study with a prodrug of galantamine: improved benefit-risk ratio? Alzheimer’s Dement Transl Res Clin Interv. 2016;2(1):13–22. DOI:https://doi.org/10.1016/j.trci.2015.12.003.
  • Bakker C, Aart J, and Hart EP, et al. Safety, pharmacokinetics, and pharmacodynamics of Gln‐1062, a prodrug of galantamine. Alzheimer’s Dement Transl Res Clin Interv. 2020;6:1. https://doi.org/10.1002/trc2.12093.
  • Xiao S, Chan P, Wang T, et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s Dementia. Alzheimers Res Ther. 2021;13(1):62.
  • Cavalli A, Bolognesi ML, Minarini A, et al. Multi-Target-Directed Ligands To Combat Neurodegenerative Diseases. J Med Chem. 2008;51(3):347–372. DOI:https://doi.org/10.1021/jm7009364.
  • Liu Z, Zhang B, Xia S, et al. ROS-responsive and multifunctional anti-alzheimer prodrugs: tacrine-Ibuprofen hybrids via a phenyl boronate linker. Eur J Med Chem. 2021;212:112997.
  • Sestito S, Daniele S, Pietrobono D, et al. Memantine prodrug as a new agent for Alzheimer’s disease. Sci Rep. 2019;9(1):4612.
  • Gong T, Huang Y, Zhang Z-R, et al. Synthesis and Characterization of 9-[P -(N, N -Dipropyl Sulfamide)] benzoylamino-1,2,3,4-4H-acridine—A potential prodrug for the CNS delivery of tacrine. J Drug Target. 2004;12(3):177–182.
  • Sozio P, Cerasa LS, Laserra S, et al. Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer’s disease. Eur J Pharm Sci. 2013;49(2):187–198.
  • Colín-González A, and Santamaría A. Probenecid: an emerging tool for neuroprotection. CNS Neurol Disord - Drug Targets. 2013;12(7):1050–1065. DOI:https://doi.org/10.2174/18715273113129990090.
  • Markowicz-Piasecka M, Sikora J, Mateusiak Ł, et al. Metformin and its Sulfenamide prodrugs inhibit human cholinesterase activity. Oxid Med Cell Longev. 2017;2017:1–11.
  • Markoutsa E, Xu P. Redox potential-sensitive n -acetyl cysteine-prodrug nanoparticles inhibit the activation of microglia and improve neuronal survival. Mol Pharm. 2017;14(5):1591–1600.
  • Purgatorio R, Candia M, Catto M, et al. Evaluation of water‐soluble mannich base prodrugs of 2,3,4,5‐tetrahydroazepino[4,3‐ b]indol‐1(6 H)‐one as multitarget‐directed agents for Alzheimer’s disease. ChemMedChem. 2021;16(3):589–598.
  • Conte-Daban A, Ambike V, Guillot R, et al. A metallo pro-drug to target Cu II in the context of Alzheimer’s disease. Chem A Eur J. 2018;24(20):5095–5099.
  • Liargkova T, Hadjipavlou-Litina DJ, Koukoulitsa C, et al. Simple chalcones and bis -chalcones ethers as possible pleiotropic agents. J Enzyme Inhib Med Chem. 2016;31(2):302–313.
  • Weinstock M, Goren T, Youdim MBH. Development of a novel neuroprotective drug (TV3326) for the treatment of Alzheimer’s disease, with cholinesterase and monoamine oxidase inhibitory activities. Drug Dev Res. 2000;50(3–4):216–222. DOI:https://doi.org/10.1002/1098-2299(200007/08)50:3/4<216::AID-DDR4>3.0.CO;2-Z.
  • Weinstock M, Bejar C, and Wang R-H, et al. TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease. In: Advances in research on neurodegeneration. Vienna: Springer; 2000. p. 157–169. DOI:https://doi.org/10.1007/978-3-7091-6301-6_10.
  • Youdim MB, Weinstock M. Molecular basis of neuroprotective activities of rasagiline and the Anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol. 2001;21(6):555–573.
  • Maruyama W, Weinstock M, Youdim MB, et al. Anti-Apoptotic Action of Anti-Alzheimer Drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-Yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. Neurosci Lett. 2003;341(3):233–236.
  • Buccafusco J, Terry A, Goren T, et al. Potential cognitive actions of (n-propargly-(3r)-aminoindan-5-Yl)-ethyl, methyl carbamate (Tv3326), a novel neuroprotective agent, as assessed in old rhesus monkeys in their performance of versions of a delayed matching task. Neuroscience. 2003;119(3):669–678.
  • Schneider LS, Geffen Y, Rabinowitz J, et al. Low-dose ladostigil for mild cognitive impairment. Neurology. 2019;93(15):e1474–e1484.
  • Do Carmo Carreiras M, Ismaili L, Marco-Contelles J. Propargylamine-Derived Multi-Target Directed Ligands for Alzheimer’s Disease Therapy. Bioorg Med Chem Lett. 2020;30(3):126880.
  • Lu C, Zhou Q, Yan J, et al. A novel series of tacrine–selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer’s disease. Eur J Med Chem. 2013;62:745–753.
  • Sun Y, Chen J, Chen X, et al. Inhibition of cholinesterase and monoamine oxidase-B Activity by tacrine–homoisoflavonoid hybrids. Bioorg Med Chem. 2013;21(23):7406–7417.
  • Wang Y, Sun Y, and Guo Y, et al. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. J Enzyme Inhib Med Chem. 2015;1–9. DOI:https://doi.org/10.3109/14756366.2015.1024675.
  • Denya I, Malan SF, Enogieru AB, et al. Design synthesis and evaluation of indole derivatives as multifunctional agents against Alzheimer’s disease. Medchemcomm. 2018;9(2):357–370.
  • Zheng H, Youdim MBH, Fridkin M. Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer’s therapy. ACS Chem Biol. 2010;5(6):603–610.
  • Huang W, Liang M, Li Q, et al. Development of the “Hidden” multifunctional agents for Alzheimer’s disease. Eur J Med Chem. 2019;177:247–258.
  • Zheng H, Youdim MBH, Fridkin M. Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective−neurorestorative moieties for Alzheimer’s Therapy. J Med Chem. 2009;52(14):4095–4098.
  • Toublet F-X, Lecoutey C, Lalut J, et al. Inhibiting acetylcholinesterase to activate pleiotropic prodrugs with therapeutic interest in Alzheimer’s disease. Molecules. 2019;24(15):2786.
  • Toublet F-X, Lalut J, Hatat B, et al. Pleiotropic prodrugs: design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer’s disease. Eur J Med Chem. 2021;210:113059.
  • Scheiner M, Hoffmann M, He F, et al. Selective pseudo-irreversible butyrylcholinesterase inhibitors transferring antioxidant moieties to the enzyme show pronounced neuroprotective efficacy in vitro and in vivo in an Alzheimer’s disease mouse model. J Med Chem. 2021;64(13):9302–9320. DOI:https://doi.org/10.1021/acs.jmedchem.1c00534.
  • Verheijen JC, Wiig KA, Du S, et al. Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition. Bioorg Med Chem Lett. 2009;19(12):3243–3246.
  • Rautio J, Meanwell NA, Di L, et al. The expanding role of Prodrugs in contemporary drug design and development. Nat Rev Drug Discov. 2018;17(8):559–587. DOI:https://doi.org/10.1038/nrd.2018.46.
  • Sweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133–150.
  • Agrawal M, Saraf S, Saraf S, et al. Nose-to-brain drug delivery: an update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J Control Release. 2018;281:139–177.
  • Adnet T, Groo A-C, Picard C, et al. Pharmacotechnical development of a nasal drug delivery composite nanosystem intended for Alzheimer’s disease treatment. Pharmaceutics. 2020;12(3):251.

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