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Current Medicinal Chemistry

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ISSN (Online): 1875-533X

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Review Article

Tackling Alzheimer’s Disease with Existing Drugs: A Promising Strategy for Bypassing Obstacles

Author(s): Angela Rampa*, Silvia Gobbi, Federica Belluti and Alessandra Bisi*

Volume 28, Issue 12, 2021

Published on: 31 August, 2020

Page: [2305 - 2327] Pages: 23

DOI: 10.2174/0929867327666200831140745

Price: $65

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Abstract

The unmet need for the development of effective drugs to treat Alzheimer's disease has been steadily growing, representing a major challenge in drug discovery. In this context, drug repurposing, namely the identification of novel therapeutic indications for approved or investigational compounds, can be seen as an attractive attempt to obtain new medications reducing both the time and the economic burden usually required for research and development programs. In the last years, several classes of drugs have evidenced promising beneficial effects in neurodegenerative diseases, and for some of them, preliminary clinical trials have been started. This review aims to illustrate some of the most recent examples of drugs reprofiled for Alzheimer’s disease, considering not only the finding of new uses for existing drugs but also the new hypotheses on disease pathogenesis that could promote previously unconsidered therapeutic regimens. Moreover, some examples of structural modifications performed on existing drugs in order to obtain multifunctional compounds will also be described.

Keywords: Drug repurposing, drug reprofiling, multitarget drug, Alzheimer's Disease, antibiotics, chelating agents, antidiabetics.

« Previous Next »
[1]
Sams-Dodd, F. Target-based drug discovery: is something wrong? Drug Discov. Today, 2005, 10(2), 139-147.
[http://dx.doi.org/10.1016/S1359-6446(04)03316-1] [PMID: 15718163]
[2]
Mei, Y.; Yang, B. Rational application of drug promiscuity in medicinal chemistry. Future Med. Chem., 2018, 10(15), 1835-1851.
[http://dx.doi.org/10.4155/fmc-2018-0018] [PMID: 30019924]
[3]
Chartier, M.; Morency, L.P.; Zylber, M.I.; Najmanovich, R.J. Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects. BMC Pharmacol. Toxicol., 2017, 18(1), 18.
[http://dx.doi.org/10.1186/s40360-017-0128-7] [PMID: 28449705]
[4]
Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem., 2005, 48(21), 6523-6543.
[http://dx.doi.org/10.1021/jm058225d] [PMID: 16220969]
[5]
Ramsay, R.R.; Popovic-Nikolic, M.R.; Nikolic, K.; Uliassi, E.; Bolognesi, M.L. A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med., 2018, 7(1), 3.
[http://dx.doi.org/10.1186/s40169-017-0181-2] [PMID: 29340951]
[6]
Ashburn, T.T.; Thor, K.B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov., 2004, 3(8), 673-683.
[http://dx.doi.org/10.1038/nrd1468] [PMID: 15286734]
[7]
Parsons, C.G. CNS repurposing - Potential new uses for old drugs: Examples of screens for Alzheimer’s disease, Parkinson’s disease and spasticity. Neuropharmacology, 2019, 147, 4-10.
[http://dx.doi.org/10.1016/j.neuropharm.2018.08.027] [PMID: 30165077]
[8]
Prince, M.; Comas-Herrera, A.; Knapp, M.; Guerchet, M.; Karagiannidou, M. World Alzheimer Report 2016: Improving healthcare for people living with dementia: Coverage, quality and costs now and in the future; Alzheimer’s Disease International, 2017. London, UK.
[9]
Alzheimer’s Association. 2019 Alzheimer’s disease facts and figures. Alzheimers Dement., 2019, 15(3), 321-387.
[http://dx.doi.org/10.1016/j.jalz.2019.01.010]
[10]
Corbett, A.; Pickett, J.; Burns, A.; Corcoran, J.; Dunnett, S.B.; Edison, P.; Hagan, J.J.; Holmes, C.; Jones, E.; Katona, C.; Kearns, I.; Kehoe, P.; Mudher, A.; Passmore, A.; Shepherd, N.; Walsh, F.; Ballard, C. Drug repositioning for Alzheimer’s disease. Nat. Rev. Drug Discov., 2012, 11(11), 833-846.
[http://dx.doi.org/10.1038/nrd3869] [PMID: 23123941]
[11]
Durães, F.; Pinto, M.; Sousa, E. Old drugs as new treatments for neurodegenerative diseases. Pharmaceuticals (Basel), 2018, 11(2), 44-65.
[http://dx.doi.org/10.3390/ph11020044] [PMID: 29751602]
[12]
Folch, J.; Petrov, D.; Ettcheto, M.; Abad, S.; Sánchez-López, E.; García, M.L.; Olloquequi, J.; Beas-Zarate, C.; Auladell, C.; Camins, A. Current research therapeutic strategies for Alzheimer’s disease treatment. Neural Plast., 2016, 20168501693
[http://dx.doi.org/10.1155/2016/8501693] [PMID: 26881137]
[13]
Willem, M.; Lammich, S.; Haass, C. Function, regulation and therapeutic properties of beta-secretase (BACE1). Semin. Cell Dev. Biol., 2009, 20(2), 175-182.
[http://dx.doi.org/10.1016/j.semcdb.2009.01.003] [PMID: 19429494]
[14]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002, 297(5580), 353-356.
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[15]
Jamieson, G.A.; Maitland, N.J.; Wilcock, G.K.; Craske, J.; Itzhaki, R.F. Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J. Med. Virol., 1991, 33(4), 224-227.
[http://dx.doi.org/10.1002/jmv.1890330403] [PMID: 1649907]
[16]
Itzhaki, R.F.; Lathe, R.; Balin, B.J.; Ball, M.J.; Bearer, E.L.; Braak, H.; Bullido, M.J.; Carter, C.; Clerici, M.; Cosby, S.L.; Del Tredici, K.; Field, H.; Fulop, T.; Grassi, C.; Griffin, W.S.; Haas, J.; Hudson, A.P.; Kamer, A.R.; Kell, D.B.; Licastro, F.; Letenneur, L.; Lövheim, H.; Mancuso, R.; Miklossy, J.; Otth, C.; Palamara, A.T.; Perry, G.; Preston, C.; Pretorius, E.; Strandberg, T.; Tabet, N.; Taylor-Robinson, S.D.; Whittum-Hudson, J.A. Microbes and Alzheimer’s Disease. J. Alzheimers Dis., 2016, 51(4), 979-984.
[http://dx.doi.org/10.3233/JAD-160152] [PMID: 26967229]
[17]
Itzhaki, R.F. A Turning point in Alzheimer’s disease: microbes matter. J. Alzheimers Dis., 2019, 72(4), 977-980.
[http://dx.doi.org/10.3233/JAD-191171] [PMID: 31815699]
[18]
Panza, F.; Lozupone, M.; Solfrizzi, V.; Watling, M.; Imbimbo, B.P. Time to test antibacterial therapy in Alzheimer’s disease. Brain, 2019, 142(10), 2905-2929.
[http://dx.doi.org/10.1093/brain/awz244] [PMID: 31532495]
[19]
Angelucci, F.; Cechova, K.; Amlerova, J.; Hort, J. Antibiotics, gut microbiota, and Alzheimer’s disease. J. Neuroinflammation, 2019, 16(1), 108-118.
[http://dx.doi.org/10.1186/s12974-019-1494-4] [PMID: 31118068]
[20]
Zhuang, Z.Q.; Shen, L.L.; Li, W.W.; Fu, X.; Zeng, F.; Gui, L.; Lü, Y.; Cai, M.; Zhu, C.; Tan, Y.L.; Zheng, P.; Li, H.Y.; Zhu, J.; Zhou, H.D.; Bu, X.L.; Wang, Y.J. Gut Microbiota is Altered in Patients with Alzheimer’s Disease. J. Alzheimers Dis., 2018, 63(4), 1337-1346.
[http://dx.doi.org/10.3233/JAD-180176] [PMID: 29758946]
[21]
Moir, R.D.; Lathe, R.; Tanzi, R.E. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement., 2018, 14(12), 1602-1614.
[http://dx.doi.org/10.1016/j.jalz.2018.06.3040] [PMID: 30314800]
[22]
Socias, S.B.; González-Lizárraga, F.; Avila, C.L.; Vera, C.; Acuña, L.; Sepulveda-Diaz, J.E.; Del-Bel, E.; Raisman-Vozari, R.; Chehin, R.N. Exploiting the therapeutic potential of ready-to-use drugs: Repurposing antibiotics against amyloid aggregation in neurodegenerative diseases. Prog. Neurobiol., 2018, 162, 17-36.
[http://dx.doi.org/10.1016/j.pneurobio.2017.12.002] [PMID: 29241812]
[23]
Santa-Cecília, F.V.; Leite, C.A.; Del-Bel, E.; Raisman-Vozari, R. The neuroprotective effect of doxycycline on neurodegenerative diseases. Neurotox. Res., 2019, 35(4), 981-986.
[http://dx.doi.org/10.1007/s12640-019-00015-z] [PMID: 30798507]
[24]
Forloni, G.; Colombo, L.; Girola, L.; Tagliavini, F.; Salmona, M. Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett., 2001, 487(3), 404-407.
[http://dx.doi.org/10.1016/S0014-5793(00)02380-2] [PMID: 11163366]
[25]
Diomede, L.; Cassata, G.; Fiordaliso, F.; Salio, M.; Ami, D.; Natalello, A.; Doglia, S.M.; De Luigi, A.; Salmona, M. Tetracycline and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting oligomers. Neurobiol. Dis., 2010, 40(2), 424-431.
[http://dx.doi.org/10.1016/j.nbd.2010.07.002] [PMID: 20637283]
[26]
Costa, R.; Speretta, E.; Crowther, D.C.; Cardoso, I. Testing the therapeutic potential of doxycycline in a Drosophila melanogaster model of Alzheimer disease. J. Biol. Chem., 2011, 286(48), 41647-41655.
[http://dx.doi.org/10.1074/jbc.M111.274548] [PMID: 21998304]
[27]
Gautieri, A.; Beeg, M.; Gobbi, M.; Rigoldi, F.; Colombo, L.; Salmona, M. The anti-amyloidogenic action of doxycycline: a molecular dynamics study on the interaction with Aβ42. Int. J. Mol. Sci., 2019, 20(18), 4641-4653.
[http://dx.doi.org/10.3390/ijms20184641] [PMID: 31546787]
[28]
Noble, W.; Garwood, C.J.; Hanger, D.P. Minocycline as a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding. Prion, 2009, 3(2), 78-83.
[http://dx.doi.org/10.4161/pri.3.2.8820] [PMID: 19458490]
[29]
Amani, M.; Shokouhi, G.; Salari, A.A. Minocycline prevents the development of depression-like behavior and hippocampal inflammation in a rat model of Alzheimer’s disease. Psychopharmacology (Berl.), 2019, 236(4), 1281-1292.
[http://dx.doi.org/10.1007/s00213-018-5137-8] [PMID: 30515523]
[30]
Howard, R.; Zubko, O.; Bradley, R.; Harper, E.; Pank, L.; O’Brien, J.; Fox, C.; Tabet, N.; Livingston, G.; Bentham, P.; McShane, R.; Burns, A.; Ritchie, C.; Reeves, S.; Lovestone, S.; Ballard, C.; Noble, W.; Nilforooshan, R.; Wilcock, G.; Gray, R. Minocycline in Alzheimer disease efficacy (MADE) Trialist group. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial. JAMA Neurol., 2020, 77(2), 164-174.
[http://dx.doi.org/10.1001/jamaneurol.2019.3762] [PMID: 31738372]
[31]
Tikhonova, M.A.; Amstislavskaya, T.G.; Belichenko, V.M.; Fedoseeva, L.A.; Kovalenko, S.P.; Pisareva, E.E.; Avdeeva, A.S.; Kolosova, N.G.; Belyaev, N.D.; Aftanas, L.I. Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties. BMC Neurosci., 2018, 19(Suppl. 1), 13.
[http://dx.doi.org/10.1186/s12868-018-0412-5] [PMID: 29745864]
[32]
Akina, S.; Thati, M.; Puchchakayala, G. Neuroprotective effect of ceftriaxone and selegiline on scopolamine induced cognitive impairment in mice. Adv. Biol. Res., 2013, 7(6), 266-275.
[http://dx.doi.org/10.5829/idosi.abr.2013.7.6.75119]
[33]
Zumkehr, J.; Rodriguez-Ortiz, C.J.; Cheng, D.; Kieu, Z.; Wai, T.; Hawkins, C.; Kilian, J.; Lim, S.L.; Medeiros, R.; Kitazawa, M. Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer’s disease. Neurobiol. Aging, 2015, 36(7), 2260-2271.
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.04.005] [PMID: 25964214]
[34]
Tai, C.H.; Bellesi, M.; Chen, A.C.; Lin, C.L.; Li, H.H.; Lin, P.J.; Liao, W.C.; Hung, C.S.; Schwarting, R.K.; Ho, Y.J. A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects. Behav. Brain Res., 2019, 364, 149-156.
[http://dx.doi.org/10.1016/j.bbr.2019.02.020] [PMID: 30768995]
[35]
Tucker, S.; Ahl, M.; Bush, A.; Westaway, D.; Huang, X.; Rogers, J.T. Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer’s APP 5′ untranslated region. Curr. Alzheimer Res., 2005, 2(2), 249-254.
[http://dx.doi.org/10.2174/1567205053585855] [PMID: 15974925]
[36]
Kountouras, J.; Boziki, M.; Gavalas, E.; Zavos, C.; Deretzi, G.; Grigoriadis, N.; Tsolaki, M.; Chatzopoulos, D.; Katsinelos, P.; Tzilves, D.; Zabouri, A.; Michailidou, I. Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer’s disease. Int. J. Neurosci., 2009, 119(6), 765-777.
[http://dx.doi.org/10.1080/00207450902782083] [PMID: 19326283]
[37]
Scofield, M.D.; Kalivas, P.W. Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. Neuroscientist, 2014, 20(6), 610-622.
[http://dx.doi.org/10.1177/1073858413520347] [PMID: 24496610]
[38]
Peyrovian, B.; Rosenblat, J.D.; Pan, Z.; Iacobucci, M.; Brietzke, E.; McIntyre, R.S. The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2019, 92, 387-404.
[http://dx.doi.org/10.1016/j.pnpbp.2019.02.001] [PMID: 30738126]
[39]
Tsai, G.E.; Falk, W.E.; Gunther, J.; Coyle, J.T. Improved cognition in Alzheimer’s disease with short-term D-cycloserine treatment. Am. J. Psychiatry, 1999, 156(3), 467-469.
[http://dx.doi.org/10.1176/ajp.156.3.467] [PMID: 10080566]
[40]
Chaturvedi, S.K.; Zaidi, N.; Alam, P.; Khan, J.M.; Qadeer, A.; Siddique, I.A.; Asmat, S.; Zaidi, Y.; Khan, R.H. Unraveling comparative anti-amyloidogenic behavior of pyrazinamide and D-Cycloserine: a mechanistic biophysical insight. PLoS One, 2015, 10(8)e0136528
[http://dx.doi.org/10.1371/journal.pone.0136528] [PMID: 26312749]
[41]
Umeda, T.; Ono, K.; Sakai, A.; Yamashita, M.; Mizuguchi, M.; Klein, W.L.; Yamada, M.; Mori, H.; Tomiyama, T. Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers. Brain, 2016, 139(Pt 5), 1568-1586.
[http://dx.doi.org/10.1093/brain/aww042] [PMID: 27020329]
[42]
Espargaró, A.; Pont, C.; Gamez, P.; Muñoz-Torrero, D.; Sabate, R. Amyloid pan-inhibitors: one family of compounds to cope with all conformational diseases. ACS Chem. Neurosci., 2019, 10(3), 1311-1317.
[http://dx.doi.org/10.1021/acschemneuro.8b00398] [PMID: 30380841]
[43]
Tomiyama, T.; Asano, S.; Suwa, Y.; Morita, T.; Kataoka, K.; Mori, H.; Endo, N. Rifampicin prevents the aggregation and neurotoxicity of amyloid β protein in vitro. Biochem. Biophys. Res. Commun., 1994, 204(1), 76-83.
[http://dx.doi.org/10.1006/bbrc.1994.2428] [PMID: 7945395]
[44]
Tomiyama, T.; Shoji, A.; Kataoka, K.; Suwa, Y.; Asano, S.; Kaneko, H.; Endo, N. Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J. Biol. Chem., 1996, 271(12), 6839-6844.
[http://dx.doi.org/10.1074/jbc.271.12.6839] [PMID: 8636108]
[45]
Camardo, J. The Rapamune era of immunosuppression 2003: the journey from the laboratory to clinical transplantation. Transplant. Proc., 2003, 35(3)(Suppl.), 18S-24S.
[http://dx.doi.org/10.1016/S0041-1345(03)00356-7] [PMID: 12742464]
[46]
Brown, E.J.; Albers, M.W.; Shin, T.B.; Ichikawa, K.; Keith, C.T.; Lane, W.S.; Schreiber, S.L. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature, 1994, 369(6483), 756-758.
[http://dx.doi.org/10.1038/369756a0] [PMID: 8008069]
[47]
Richardson, A.; Galvan, V.; Lin, A.L.; Oddo, S. How longevity research can lead to therapies for Alzheimer’s disease: The rapamycin story. Exp. Gerontol., 2015, 68, 51-58.
[http://dx.doi.org/10.1016/j.exger.2014.12.002] [PMID: 25481271]
[48]
Kaye, E.K.; Valencia, A.; Baba, N.; Spiro, A., III; Dietrich, T.; Garcia, R.I. Tooth loss and periodontal disease predict poor cognitive function in older men. J. Am. Geriatr. Soc., 2010, 58(4), 713-718.
[http://dx.doi.org/10.1111/j.1532-5415.2010.02788.x] [PMID: 20398152]
[49]
Dominy, S.S.; Lynch, C.; Ermini, F.; Benedyk, M.; Marczyk, A.; Konradi, A.; Nguyen, M.; Haditsch, U.; Raha, D.; Griffin, C.; Holsinger, L.J.; Arastu-Kapur, S.; Kaba, S.; Lee, A.; Ryder, M.I.; Potempa, B.; Mydel, P.; Hellvard, A.; Adamowicz, K.; Hasturk, H.; Walker, G.D.; Reynolds, E.C.; Faull, R.L.M.; Curtis, M.A.; Dragunow, M.; Potempa, J. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv., 2019, 5(1)eaau3333
[http://dx.doi.org/10.1126/sciadv.aau3333] [PMID: 30746447]
[50]
Qin, Q.; Li, Y. Herpesviral infections and antimicrobial protection for Alzheimer’s disease: Implications for prevention and treatment. J. Med. Virol., 2019, 91(8), 1368-1377.
[http://dx.doi.org/10.1002/jmv.25481] [PMID: 30997676]
[51]
Allnutt, M.A.; Johnson, K.; Bennett, D.A.; Connor, S.M.; Troncoso, J.C.; Pletnikova, O.; Albert, M.S.; Resnick, S.M.; Scholz, S.W.; De Jager, P.L.; Jacobson, S. Human Herpesvirus 6 detection in Alzheimer’s disease cases and controls across multiple cohorts. Neuron, 2020, 105(6), 1027-1035.e2.
[http://dx.doi.org/10.1016/j.neuron.2019.12.031] [PMID: 31983538]
[52]
Wozniak, M.A.; Frost, A.L.; Preston, C.M.; Itzhaki, R.F. Antivirals reduce the formation of key Alzheimer’s disease molecules in cell cultures acutely infected with herpes simplex virus type 1. PLoS One, 2011, 6(10)e25152
[http://dx.doi.org/10.1371/journal.pone.0025152] [PMID: 22003387]
[53]
Kimura, T.; Goto, M. Existence of senile plaques in the brains of elderly leprosy patients. Lancet, 1993, 342(8883), 1364.
[http://dx.doi.org/10.1016/0140-6736(93)92274-W] [PMID: 7901655]
[54]
Van Gool, W.A.; Weinstein, H.C.; Scheltens, P.; Walstra, G.J. Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet, 2001, 358(9280), 455-460.
[http://dx.doi.org/10.1016/S0140-6736(01)05623-9] [PMID: 11513909]
[55]
Zatta, P.; Drago, D.; Bolognin, S.; Sensi, S.L. Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol. Sci., 2009, 30(7), 346-355.
[http://dx.doi.org/10.1016/j.tips.2009.05.002] [PMID: 19540003]
[56]
Grossi, C.; Francese, S.; Casini, A.; Rosi, M.C.; Luccarini, I.; Fiorentini, A.; Gabbiani, C.; Messori, L.; Moneti, G.; Casamenti, F. Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer’s disease. J. Alzheimers Dis., 2009, 17(2), 423-440.
[http://dx.doi.org/10.3233/JAD-2009-1063] [PMID: 19363260]
[57]
García-Osta, A.; Cuadrado-Tejedor, M.; García-Barroso, C.; Oyarzábal, J.; Franco, R. Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem. Neurosci., 2012, 3(11), 832-844.
[http://dx.doi.org/10.1021/cn3000907] [PMID: 23173065]
[58]
Chen, S.K.; Zhao, P.; Shao, Y.X.; Li, Z.; Zhang, C.; Liu, P.; He, X.; Luo, H.B.; Hu, X. Moracin M from Morus alba L. is a natural phosphodiesterase-4 inhibitor. Bioorg. Med. Chem. Lett., 2012, 22(9), 3261-3264.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.026] [PMID: 22483586]
[59]
Fernández-Bachiller, M.I.; Pérez, C.; González-Muñoz, G.C.; Conde, S.; López, M.G.; Villarroya, M.; García, A.G.; Rodríguez-Franco, M.I. Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer’s disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J. Med. Chem., 2010, 53(13), 4927-4937.
[http://dx.doi.org/10.1021/jm100329q] [PMID: 20545360]
[60]
Antequera, D.; Bolos, M.; Spuch, C.; Pascual, C.; Ferrer, I.; Fernandez-Bachiller, M.I.; Rodríguez-Franco, M.I.; Carro, E. Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Aβ accumulation and cell death: involvement in hippocampal neuronal loss in Alzheimer’s disease. Neurobiol. Dis., 2012, 46(3), 682-691.
[http://dx.doi.org/10.1016/j.nbd.2012.03.009] [PMID: 22426395]
[61]
Prati, F.; Bergamini, C.; Fato, R.; Soukup, O.; Korabecny, J.; Andrisano, V.; Bartolini, M.; Bolognesi, M.L. Novel 8-hydroxyquinoline derivatives as multitarget compounds for the treatment of Alzheimer’s disease. ChemMedChem, 2016, 11(12), 1284-1295.
[http://dx.doi.org/10.1002/cmdc.201600014] [PMID: 26880501]
[62]
Wang, Z.; Wang, Y.; Wang, B.; Li, W.; Huang, L.; Li, X. Design, synthesis, and evaluation of orally available clioquinol-moracin M hybrids as multitarget-directed ligands for cognitive improvement in a rat model of neurodegeneration in Alzheimer’s disease. J. Med. Chem., 2015, 58(21), 8616-8637.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01222] [PMID: 26473791]
[63]
Wang, Z.; Cao, M.; Xiang, H.; Wang, W.; Feng, X.; Yang, X. WBQ5187, a multitarget directed agent, ameliorates cognitive impairment in a transgenic mouse model of Alzheimer’s disease and modulates cerebral β Amyloid, gliosis, cAMP levels, and neurodegeneration. ACS Chem. Neurosci., 2019, 10(12), 4787-4799.
[http://dx.doi.org/10.1021/acschemneuro.9b00409] [PMID: 31697472]
[64]
Hu, J.; Pan, T.; An, B.; Li, Z.; Li, X.; Huang, L. Synthesis and evaluation of clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2019, 163, 512-526.
[http://dx.doi.org/10.1016/j.ejmech.2018.12.013] [PMID: 30553143]
[65]
Mao, F.; Yan, J.; Li, J.; Jia, X.; Miao, H.; Sun, Y.; Huang, L.; Li, X. New multi-target-directed small molecules against Alzheimer’s disease: a combination of resveratrol and clioquinol. Org. Biomol. Chem., 2014, 12(31), 5936-5944.
[http://dx.doi.org/10.1039/C4OB00998C] [PMID: 24986600]
[66]
Rajasekhar, K.; Mehta, K.; Govindaraju, T. Hybrid multifunctional modulators inhibit multifaceted Aβ toxicity and prevent mitochondrial damage. ACS Chem. Neurosci., 2018, 9(6), 1432-1440.
[http://dx.doi.org/10.1021/acschemneuro.8b00033] [PMID: 29557650]
[67]
Di Giovanni, S.; Eleuteri, S.; Paleologou, K.E.; Yin, G.; Zweckstetter, M.; Carrupt, P.A.; Lashuel, H.A. Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of α-synuclein and β-amyloid and protect against amyloid-induced toxicity. J. Biol. Chem., 2010, 285(20), 14941-14954.
[http://dx.doi.org/10.1074/jbc.M109.080390] [PMID: 20150427]
[68]
Mohamed, T.; Hoang, T.; Jelokhani-Niaraki, M.; Rao, P.P.N. Tau-derived-hexapeptide 306VQIVYK311 aggregation inhibitors: nitrocatechol moiety as a pharmacophore in drug design. ACS Chem. Neurosci., 2013, 4(12), 1559-1570.
[http://dx.doi.org/10.1021/cn400151a] [PMID: 24007550]
[69]
Bastianetto, S.; Krantic, S.; Quirion, R. Polyphenols as potential inhibitors of amyloid aggregation and toxicity: possible significance to Alzheimer’s disease. Mini Rev. Med. Chem., 2008, 8(5), 429-435.
[http://dx.doi.org/10.2174/138955708784223512] [PMID: 18473932]
[70]
Silva, T.; Mohamed, T.; Shakeri, A.; Rao, P.P.N.; Soares da Silva, P.; Remião, F.; Borges, F. Repurposing nitrocatechols: 5-Nitro-α-cyanocarboxamide derivatives of caffeic acid and caffeic acid phenethyl ester effectively inhibit aggregation of tau-derived hexapeptide AcPHF6. Eur. J. Med. Chem., 2019, 167, 146-152.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.006] [PMID: 30771602]
[71]
Lanza, V.; Milardi, D.; Di Natale, G.; Pappalardo, G. Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases. Curr. Med. Chem., 2018, 25(4), 525-539.
[http://dx.doi.org/10.2174/0929867324666170518094404] [PMID: 28521682]
[72]
Candeias, E.; Duarte, A.I.; Carvalho, C.; Correia, S.C.; Cardoso, S.; Santos, R.X.; Plácido, A.I.; Perry, G.; Moreira, P.I. The impairment of insulin signaling in Alzheimer’s disease. IUBMB Life, 2012, 64(12), 951-957.
[http://dx.doi.org/10.1002/iub.1098] [PMID: 23129399]
[73]
Hsu, C.C.; Wahlqvist, M.L.; Lee, M.S.; Tsai, H.N. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J. Alzheimers Dis., 2011, 24(3), 485-493.
[http://dx.doi.org/10.3233/JAD-2011-101524] [PMID: 21297276]
[74]
Cheng, C.; Lin, C.H.; Tsai, Y.W.; Tsai, C.J.; Chou, P.H.; Lan, T.H. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(10), 1299-1305.
[http://dx.doi.org/10.1093/gerona/glu073] [PMID: 24899525]
[75]
Chen, Y.; Zhou, K.; Wang, R.; Liu, Y.; Kwak, Y.D.; Ma, T.; Thompson, R.C.; Zhao, Y.; Smith, L.; Gasparini, L.; Luo, Z.; Xu, H.; Liao, F.F. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc. Natl. Acad. Sci. USA, 2009, 106(10), 3907-3912.
[http://dx.doi.org/10.1073/pnas.0807991106] [PMID: 19237574]
[76]
Escribano, L.; Simón, A-M.; Gimeno, E.; Cuadrado-Tejedor, M.; López de Maturana, R.; García-Osta, A.; Ricobaraza, A.; Pérez-Mediavilla, A.; Del Río, J.; Frechilla, D. Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology, 2010, 35(7), 1593-1604.
[http://dx.doi.org/10.1038/npp.2010.32] [PMID: 20336061]
[77]
Papadopoulos, P.; Rosa-Neto, P.; Rochford, J.; Hamel, E. Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer’s disease with combined amyloid-β and cerebrovascular pathology. PLoS One, 2013, 8(7)e68612
[http://dx.doi.org/10.1371/journal.pone.0068612] [PMID: 23874687]
[78]
Gold, M.; Alderton, C.; Zvartau-Hind, M.; Egginton, S.; Saunders, A.M.; Irizarry, M.; Craft, S.; Landreth, G.; Linnamägi, U.; Sawchak, S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement. Geriatr. Cogn. Disord., 2010, 30(2), 131-146.
[http://dx.doi.org/10.1159/000318845] [PMID: 20733306]
[79]
Chang, K.L.; Pee, H.N.; Yang, S.; Ho, P.C. Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer’s disease. Sci. Rep., 2015, 5, 9000.
[http://dx.doi.org/10.1038/srep09000] [PMID: 25760794]
[80]
Chen, J.; Li, S.; Sun, W.; Li, J. Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity. PLoS One, 2015, 10(4)e0123864
[http://dx.doi.org/10.1371/journal.pone.0123864] [PMID: 25875370]
[81]
Searcy, J.L.; Phelps, J.T.; Pancani, T.; Kadish, I.; Popovic, J.; Anderson, K.L.; Beckett, T.L.; Murphy, M.P.; Chen, K-C.; Blalock, E.M.; Landfield, P.W.; Porter, N.M.; Thibault, O. Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer’s disease. J. Alzheimers Dis., 2012, 30(4), 943-961.
[http://dx.doi.org/10.3233/JAD-2012-111661] [PMID: 22495349]
[82]
Cho, D.H.; Lee, E.J.; Kwon, K.J.; Shin, C.Y.; Song, K.H.; Park, J.H.; Jo, I.; Han, S.H. Troglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neurons. J. Neurochem., 2013, 126(5), 685-695.
[http://dx.doi.org/10.1111/jnc.12264] [PMID: 23581463]
[83]
Jojo, G.M.; Kuppusamy, G.; De, A.; Karri, V.V.S.N.R. Formulation and optimization of intranasal nanolipid carriers of pioglitazone for the repurposing in Alzheimer’s disease using Box-Behnken design. Drug Dev. Ind. Pharm., 2019, 45(7), 1061-1072.
[http://dx.doi.org/10.1080/03639045.2019.1593439] [PMID: 30922126]
[84]
Fernandez-Martos, C.M.; Atkinson, R.A.K.; Chuah, M.I.; King, A.E.; Vickers, J.C. Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer’s disease. Alzheimers Dement. (N. Y.), 2016, 3(1), 92-106.
[http://dx.doi.org/10.1016/j.trci.2016.11.002] [PMID: 29067321]
[85]
Skerrett, R.; Pellegrino, M.P.; Casali, B.T.; Taraboanta, L.; Landreth, G.E. Combined liver X receptor/peroxisome proliferatoractivated receptor γ agonist treatment reduces amyloid β levels and improves behavior in amyloid precursor protein/presenilin 1 mice. J. Biol. Chem., 2015, 290(35), 21591-21602.
[http://dx.doi.org/10.1074/jbc.M115.652008] [PMID: 26163517]
[86]
Whitmer, R.A.; Sidney, S.; Selby, J.; Johnston, S.C.; Yaffe, K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology, 2005, 64(2), 277-281.
[http://dx.doi.org/10.1212/01.WNL.0000149519.47454.F2] [PMID: 15668425]
[87]
Kehoe, P.G. The coming of age of the angiotensin hypothesis in Alzheimer’s disease: progress toward disease prevention and treatment? J. Alzheimers Dis., 2018, 62(3), 1443-1466.
[http://dx.doi.org/10.3233/JAD-171119] [PMID: 29562545]
[88]
Kanaide, H.; Ichiki, T.; Nishimura, J.; Hirano, K. Cellular mechanism of vasoconstriction induced by angiotensin II: it remains to be determined. Circ. Res., 2003, 93(11), 1015-1017.
[http://dx.doi.org/10.1161/01.RES.0000105920.33926.60] [PMID: 14645130]
[89]
Reaux, A.; Iturrioz, X.; Vazeux, G.; Fournie-Zaluski, M.C.; David, C.; Roques, B.P.; Corvol, P.; Llorens-Cortes, C. Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure. Biochem. Soc. Trans., 2000, 28(4), 435-440.
[PMID: 10961935]
[90]
Dupont, A.G.; Yang, R.; Smolders, I.; Vanderheyden, P. IRAP and AT(1) receptor mediated effects of angiotensin IV. J. Intern. Med., 2009, 265(3), 401-403.
[http://dx.doi.org/10.1111/j.1365-2796.2008.02027.x] [PMID: 19207373]
[91]
Ganten, D.; Marquez-Julio, A.; Granger, P.; Hayduk, K.; Karsunky, K.P.; Boucher, R.; Genest, J. Renin in dog brain. Am. J. Physiol., 1971, 221(6), 1733-1737.
[http://dx.doi.org/10.1152/ajplegacy.1971.221.6.1733] [PMID: 4330904]
[92]
Fazal, K.; Perera, G.; Khondoker, M.; Howard, R.; Stewart, R. Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer’s disease. BJPsych Open, 2017, 3(4), 158-164.
[http://dx.doi.org/10.1192/bjpo.bp.116.004184] [PMID: 28713585]
[93]
Kaur, P.; Muthuraman, A.; Kaur, M. The implications of angiotensin-converting enzymes and their modulators in neurodegenerative disorders: current and future perspectives. ACS Chem. Neurosci., 2015, 6(4), 508-521.
[http://dx.doi.org/10.1021/cn500363g] [PMID: 25680080]
[94]
Asraf, K.; Torika, N.; Apte, R.N.; Fleisher-Berkovich, S. Microglial activation is modulated by captopril: in Vitro and in Vivo studies. Front. Cell. Neurosci., 2018, 12, 116.
[http://dx.doi.org/10.3389/fncel.2018.00116] [PMID: 29765306]
[95]
Ongali, B.; Nicolakakis, N.; Tong, X.K.; Aboulkassim, T.; Papadopoulos, P.; Rosa-Neto, P.; Lecrux, C.; Imboden, H.; Hamel, E. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model. Neurobiol. Dis., 2014, 68, 126-136.
[http://dx.doi.org/10.1016/j.nbd.2014.04.018] [PMID: 24807206]
[96]
Shindo, T.; Takasaki, K.; Uchida, K.; Onimura, R.; Kubota, K.; Uchida, N.; Irie, K.; Katsurabayashi, S.; Mishima, K.; Nishimura, R.; Fujiwara, M.; Iwasaki, K. Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer’s disease incorporating additional cerebrovascular disease factors. Biol. Pharm. Bull., 2012, 35(12), 2141-2147.
[http://dx.doi.org/10.1248/bpb.b12-00387] [PMID: 23207766]
[97]
Villapol, S.; Yaszemski, A.K.; Logan, T.T.; Sánchez-Lemus, E.; Saavedra, J.M.; Symes, A.J. Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Neuropsychopharmacology, 2012, 37(13), 2817-2829.
[http://dx.doi.org/10.1038/npp.2012.152] [PMID: 22892395]
[98]
Villapol, S.; Saavedra, J.M. Neuroprotective effects of angiotensin receptor blockers. Am. J. Hypertens., 2015, 28(3), 289-299.
[http://dx.doi.org/10.1093/ajh/hpu197] [PMID: 25362113]
[99]
Wang, Z.F.; Li, J.; Ma, C.; Huang, C.; Li, Z.Q. Telmisartan ameliorates Aβ oligomer-induced inflammation via PPARγ/PTEN pathway in BV2 microglial cells. Biochem. Pharmacol., 2020, 171113674
[http://dx.doi.org/10.1016/j.bcp.2019.113674] [PMID: 31634455]
[100]
Braszko, J.J.; Walesiuk, A.; Wielgat, P. Cognitive effects attributed to angiotensin II may result from its conversion to angiotensin IV. J. Renin Angiotensin Aldosterone Syst., 2006, 7(3), 168-174.
[http://dx.doi.org/10.3317/jraas.2006.027] [PMID: 17094054]
[101]
Royea, J.; Zhang, L.; Tong, X.K.; Hamel, E. Angiotensin IV receptors mediate the cognitive and cerebrovascular benefits of losartan in a mouse model of Alzheimer’s disease. J. Neurosci., 2017, 37(22), 5562-5573.
[http://dx.doi.org/10.1523/JNEUROSCI.0329-17.2017] [PMID: 28476949]
[102]
Siddiqi, F.H.; Menzies, F.M.; Lopez, A.; Stamatakou, E.; Karabiyik, C.; Ureshino, R.; Ricketts, T.; Jimenez-Sanchez, M.; Esteban, M.A.; Lai, L.; Tortorella, M.D.; Luo, Z.; Liu, H.; Metzakopian, E.; Fernandes, H.J.R.; Bassett, A.; Karran, E.; Miller, B.L.; Fleming, A.; Rubinsztein, D.C. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat. Commun., 2019, 10(1), 1817.
[http://dx.doi.org/10.1038/s41467-019-09494-2] [PMID: 31000720]
[103]
Paris, D.; Bachmeier, C.; Patel, N.; Quadros, A.; Volmar, C.H.; Laporte, V.; Ganey, J.; Beaulieu-Abdelahad, D.; Ait-Ghezala, G.; Crawford, F.; Mullan, M.J. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier. Mol. Med., 2011, 17(3-4), 149-162.
[http://dx.doi.org/10.2119/molmed.2010.00180] [PMID: 21170472]
[104]
McCarthy, H.; Kennelly, S.; Crawford, F.; Mullan, M.; Cregg, F.; Lawlor, B.A. Repurposing nilvadipine for treatment of dementia: an overview. Drugs Future, 2017, 42(5), 281-284.
[http://dx.doi.org/10.1358/dof.2017.042.05.2625238]
[105]
Lawlor, B.; Segurado, R.; Kennelly, S.; Olde Rikkert, M.G.M.; Howard, R.; Pasquier, F.; Börjesson-Hanson, A.; Tsolaki, M.; Lucca, U.; Molloy, D.W.; Coen, R.; Riepe, M.W.; Kálmán, J.; Kenny, R.A.; Cregg, F.; O’Dwyer, S.; Walsh, C.; Adams, J.; Banzi, R.; Breuilh, L.; Daly, L.; Hendrix, S.; Aisen, P.; Gaynor, S.; Sheikhi, A.; Taekema, D.G.; Verhey, F.R.; Nemni, R.; Nobili, F.; Franceschi, M.; Frisoni, G.; Zanetti, O.; Konsta, A.; Anastasios, O.; Nenopoulou, S.; Tsolaki-Tagaraki, F.; Pakaski, M.; Dereeper, O.; de la Sayette, V.; Sénéchal, O.; Lavenu, I.; Devendeville, A.; Calais, G.; Crawford, F.; Mullan, M. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med., 2018, 15(9)e1002660
[http://dx.doi.org/10.1371/journal.pmed.1002660] [PMID: 30248105]
[106]
Liu, D.Z.; Sharp, F.R.; Van, K.C.; Ander, B.P.; Ghiasvand, R.; Zhan, X.; Stamova, B.; Jickling, G.C.; Lyeth, B.G. Inhibition of SRC family kinases protects hippocampal neurons and improves cognitive function after traumatic brain injury. J. Neurotrauma, 2014, 31(14), 1268-1276.
[http://dx.doi.org/10.1089/neu.2013.3250] [PMID: 24428562]
[107]
Bonda, D.J.; Lee, H.P.; Kudo, W.; Zhu, X.; Smith, M.A.; Lee, H.G. Pathological implications of cell cycle re-entry in Alzheimer disease. Expert Rev. Mol. Med., 2010, 12e19
[http://dx.doi.org/10.1017/S146239941000150X] [PMID: 20584423]
[108]
Nygaard, H.B.; van Dyck, C.H.; Strittmatter, S.M. Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimers Res. Ther., 2014, 6(1), 8.
[http://dx.doi.org/10.1186/alzrt238] [PMID: 24495408]
[109]
Wani, M.C.; Taylor, H.L.; Wall, M.E.; Coggon, P.; McPhail, A.T. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc., 1971, 93(9), 2325-2327.
[http://dx.doi.org/10.1021/ja00738a045] [PMID: 5553076]
[110]
Schiff, P.B.; Horwitz, S.B. Taxol stabilizes microtubules in mouse fibroblast cells. Proc. Natl. Acad. Sci. USA, 1980, 77(3), 1561-1565.
[http://dx.doi.org/10.1073/pnas.77.3.1561] [PMID: 6103535]
[111]
Varidaki, A.; Hong, Y.; Coffey, E.T. Repositioning Microtubule Stabilizing Drugs for Brain Disorders. Front. Cell. Neurosci., 2018, 12, 226.
[http://dx.doi.org/10.3389/fncel.2018.00226] [PMID: 30135644]
[112]
Kar, S.; Fan, J.; Smith, M.J.; Goedert, M.; Amos, L.A. Repeat motifs of tau bind to the insides of microtubules in the absence of taxol. EMBO J., 2003, 22(1), 70-77.
[http://dx.doi.org/10.1093/emboj/cdg001] [PMID: 12505985]
[113]
Abidi, A. Cabazitaxel: A novel taxane for metastatic castration-resistant prostate cancer-current implications and future prospects. J. Pharmacol. Pharmacother., 2013, 4(4), 230-237.
[http://dx.doi.org/10.4103/0976-500X.119704] [PMID: 24250198]
[114]
Ghoochani, A.; Hatipoglu Majernik, G.; Sehm, T.; Wach, S.; Buchfelder, M.; Taubert, H.; Eyupoglu, I.Y.; Savaskan, N. Cabazitaxel operates anti-metastatic and cytotoxic via apoptosis induction and stalls brain tumor angiogenesis. Oncotarget, 2016, 7(25), 38306-38318.
[http://dx.doi.org/10.18632/oncotarget.9439] [PMID: 27203678]
[115]
Hoefle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. Epothilone, deren herstellungsverfahren sowie sie enthaltende mittel. DE4138042A1, September 19, 1992.
[116]
Paranjpe, M.D.; Taubes, A.; Sirota, M. Insights into computational drug repurposing for neurodegenerative disease. Trends Pharmacol. Sci., 2019, 40(8), 565-576.
[http://dx.doi.org/10.1016/j.tips.2019.06.003] [PMID: 31326236]

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