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Review Article

阿尔茨海默氏病：相关靶标，可用药物的合成，正在开发的生物活性化合物以及通过多靶标方法获得的有希望的结果

卷 22, 期 5, 2021

发表于: 19 August, 2020

页: [505 - 538] 页: 34

弟呕挨: 10.2174/1389450121999200819144544

价格: $65

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摘要

我们在这里描述了与阿尔茨海默氏病有关的治疗靶标以及可用的药物及其合成途径。 还在开发中的生物活性化合物也被用于说明阿尔茨海默氏病药物化学的一些最新研究进展，包括某些靶标的构效关系。 多目标方法的重要性，包括我们研究项目中的一些例子，为寻找更有效的候选药物提供了新的视角。 这次审查包括2001年至2020年初之间的时期。

关键词: 阿尔茨海默氏病，构效关系，多靶标配体，乙酰胆碱酯酶，烟碱乙酰胆碱受体，合成途径。

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[1]
Hippius H, Neundörfer G. The discovery of Alzheimer’s disease. Dialogues Clin Neurosci 2003; 5(1): 101-8.
[PMID: 22034141]
[2]
Dineley KT, Pandya AA, Yakel JL. Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 2015; 36(2): 96-108.
[http://dx.doi.org/10.1016/j.tips.2014.12.002] [PMID: 25639674]
[3]
Cheng Q, Yakel JL. The effect of α7 nicotinic receptor activation on glutamatergic transmission in the hippocampus. Biochem Pharmacol 2015; 97(4): 439-44.
[http://dx.doi.org/10.1016/j.bcp.2015.07.015] [PMID: 26212541]
[4]
Galvez B, Gross N, Sumikawa K. Activation of α7 nicotinic acetylcholine receptors protects potentiated synapses from depotentiation during theta pattern stimulation in the hippocampal CA1 region of rats. Neuropharmacology 2016; 105: 378-87.
[http://dx.doi.org/10.1016/j.neuropharm.2016.02.008] [PMID: 26867505]
[5]
Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 2010; 19(R1): R12-20.
[http://dx.doi.org/10.1093/hmg/ddq160] [PMID: 20413653]
[6]
Kumar K, Kumar A, Keegan RM, Deshmukh R. Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease. Biomed Pharmacother 2018; 98: 297-307.
[http://dx.doi.org/10.1016/j.biopha.2017.12.053] [PMID: 29274586]
[7]
Juma KK. A current understanding of Alzheimer’s disease and the prospects of phytopharmacological intervention as a management strategy. J Neurol Disord 2015; 3: 1-7.
[8]
Harris JR, Fahrenholz F. Alzheimer’s disease: Cellular and Molecular Aspects of Amyloid Beta, Subcellular Biochemistry 38. 1st ed. Springer 2005.
[9]
Cummings JL, Isaacson RS, Schmitt FA, Velting DM. A practical algorithm for managing Alzheimer’s disease: what, when, and why? Ann Clin Transl Neurol 2015; 2(3): 307-23.
[http://dx.doi.org/10.1002/acn3.166] [PMID: 25815358]
[10]
Molino I, Colucci L, Fasanaro AM, Traini E, Amenta F. Efficacy of memantine, donepezil, or their association in moderate-severe Alzheimer’s disease: a review of clinical trials. ScientificWorldJournal 2013; 2013925702
[http://dx.doi.org/10.1155/2013/925702] [PMID: 24288512]
[11]
León R, Garcia AG, Marco-Contelles J. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med Res Rev 2013; 33(1): 139-89.
[http://dx.doi.org/10.1002/med.20248] [PMID: 21793014]
[12]
Viegas FPD, Simões MCR, Rocha MD, Castelli MR, Moreira MS, Viegas-Jr C. Doença de Alzheimer: Caracterização, Evolução e Implicações do Processo Neuroinflamatório. Rev Virtual Quim 2011; 3: 286-306.
[http://dx.doi.org/10.5935/1984-6835.20110034]
[13]
Cuny GD. Foreword: neurodegenerative diseases: challenges and opportunities. Future Med Chem 2012; 4(13): 1647-9.
[http://dx.doi.org/10.4155/fmc.12.123] [PMID: 22924500]
[14]
Dias KST, Viegas C Jr. Multi-Target Directed Drugs: A Modern Approach for Design of New Drugs for the treatment of Alzheimer’s Disease. Curr Neuropharmacol 2014; 12(3): 239-55.
[http://dx.doi.org/10.2174/1570159X1203140511153200] [PMID: 24851088]
[15]
da Rocha MD, Viegas FPD, Campos HC, et al. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders II: Alzheimer’s disease. CNS Neurol Disord Drug Targets 2011; 10(2): 251-70.
[http://dx.doi.org/10.2174/187152711794480429] [PMID: 20874701]
[16]
Campos HC, da Rocha MD, Viegas FPD, et al. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders I: Parkinson’s disease. CNS Neurol Disord Drug Targets 2011; 10(2): 239-50.
[http://dx.doi.org/10.2174/187152711794480483] [PMID: 20874702]
[17]
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]
[18]
Nesi G, Sestito S, Digiacomo M, Rapposelli S. Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer’s Disease. Curr Top Med Chem 2017; 17(27): 3062-79.
[PMID: 28595557]
[19]
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): 2583-8.
[http://dx.doi.org/10.2174/0929867311320200006] [PMID: 23590711]
[20]
Sanabria-Castro A, Alvarado-Echeverría I, Monge-Bonilla C. Molecular Pathogenesis of Alzheimer’s Disease: An Update. Ann Neurosci 2017; 24(1): 46-54.
[http://dx.doi.org/10.1159/000464422] [PMID: 28588356]
[21]
Duce JA, Tsatsanis A, Cater MA, et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 2010; 142(6): 857-67.
[http://dx.doi.org/10.1016/j.cell.2010.08.014] [PMID: 20817278]
[22]
Sun XY, Wei YP, Xiong Y, et al. Synaptic released zinc promotes tau hyperphosphorylation by inhibition of protein phosphatase 2A (PP2A). J Biol Chem 2012; 287(14): 11174-82.
[http://dx.doi.org/10.1074/jbc.M111.309070] [PMID: 22334661]
[23]
Cristóvão JS, Santos R, Gomes CM. Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease. Oxid Med Cell Longev 2016; 20169812178
[http://dx.doi.org/10.1155/2016/9812178] [PMID: 26881049]
[24]
Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci 2013; 34(6): 340-6.
[http://dx.doi.org/10.1016/j.tips.2013.04.005] [PMID: 23664668]
[25]
Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med 2004; 42(9): 1032-5.
[http://dx.doi.org/10.1515/CCLM.2004.208] [PMID: 15497469]
[26]
Cavalli A, Bolognesi ML, Minarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008; 51(3): 347-72.
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[27]
Liu X, Zhu F, Ma XH, et al. Predicting targeted polypharmacology for drug repositioning and multi- target drug discovery. Curr Med Chem 2013; 20(13): 1646-61.
[http://dx.doi.org/10.2174/0929867311320130005] [PMID: 23410165]
[28]
Carreiras MC, Mendes E, Perry MJ, Francisco AP, Marco-Contelles J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr Top Med Chem 2013; 13(15): 1745-70.
[http://dx.doi.org/10.2174/15680266113139990135] [PMID: 23931435]
[29]
Agis-Torres A, Sölhuber M, Fernandez M, Sanchez-Montero JM. Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer’s Disease. Curr Neuropharmacol 2014; 12(1): 2-36.
[http://dx.doi.org/10.2174/1570159X113116660047] [PMID: 24533013]
[30]
Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 2013; 11(3): 315-35.
[http://dx.doi.org/10.2174/1570159X11311030006] [PMID: 24179466]
[31]
Ferreira-Vieira TH, Guimarães IM, Silva FR, Ribeiro FM. Alzheimer’s disease: Targeting the Cholinergic System. Curr Neuropharmacol 2016; 14(1): 101-15.
[http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]
[32]
Acetylcholinesterase TV. Mechanism of Catalysis and Inhibition Curr Med Chem 2001; 1: 155-70.
[33]
García-Ayllón MS, Small DH, Avila J, Sáez-Valero J. Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Front Mol Neurosci 2011; 4: 22.
[http://dx.doi.org/10.3389/fnmol.2011.00022] [PMID: 21949503]
[34]
Nave S, Doody RS, Boada M, et al. Sembragiline in moderate Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase II trial. J Alzheimers Dis 2017; 58(4): 1217-28.
[http://dx.doi.org/10.3233/JAD-161309] [PMID: 28550255]
[35]
Rafii MS, Walsh S, Little JT, et al. Alzheimer’s Disease Cooperative Study. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology 2011; 76(16): 1389-94.
[http://dx.doi.org/10.1212/WNL.0b013e318216eb7b] [PMID: 21502597]
[36]
Early Diagnosis and Early Treatment of Alzheimer's Disease Based on Senile Plaque Imaging ClinicalTrials.gov Identifier: NCT02931136, 2020.
[37]
Costanzo P, Cariati L, Desiderio D, et al. Design, synthesis and evaluation of donepezil-like compounds as AChE and BACE-1 inhibitors. ACS Med Chem Lett 2016; 7(5): 470-5.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00483] [PMID: 27190595]
[38]
Lombardo S, Maskos U. Role of the nicotinic acetylcholine receptor in Alzheimer’s disease pathology and treatment. Neuropharmacology 2015; 96(Pt B): 255-62.
[http://dx.doi.org/10.1016/j.neuropharm.2014.11.018] [PMID: 25514383]
[39]
Sadigh-Eteghad S, Mahmoudi J, Babri S, Talebi M. Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function. Acta Cir Bras 2015; 30(11): 736-42.
[http://dx.doi.org/10.1590/S0102-865020150110000003] [PMID: 26647792]
[40]
Atzori M, Oscos FG, Arias HR. α7 Nicotinic acetylcholine receptor mediated anti-inflammatory actions modulate brain functions. Neutransmitter 2016; 3: 1-15.
[41]
Oz M, Lorke DE, Yang KH, Petroianu G. On the interaction of β-amyloid peptides and α7-nicotinic acetylcholine receptors in Alzheimer’s disease. Curr Alzheimer Res 2013; 10(6): 618-30.
[http://dx.doi.org/10.2174/15672050113109990132] [PMID: 23627750]
[42]
Wang X, Lippi G, Carlson DM, Berg DK. Activation of α7-containing nicotinic receptors on astrocytes triggers AMPA receptor recruitment to glutamatergic synapses. J Neurochem 2013; 127(5): 632-43.
[http://dx.doi.org/10.1111/jnc.12436] [PMID: 24032433]
[43]
Feuerbach D, Pezous N, Weiss M, et al. AQW051, a novel, potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation. Br J Phar 2014; 172: 1292-304.
[http://dx.doi.org/10.1111/bph.13001]
[44]
Mazurov AA, Speake JD, Yohannes D. Discovery and development of α7 nicotinic acetylcholine receptor modulators. J Med Chem 2011; 54(23): 7943-61.
[http://dx.doi.org/10.1021/jm2007672] [PMID: 21919481]
[45]
Huang M, Felix AR, Flood DG, et al. The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. Psychopharmacology (Berl) 2014; 231(23): 4541-51.
[http://dx.doi.org/10.1007/s00213-014-3596-0] [PMID: 24810107]
[46]
Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci 2020; 27(1): 18.
[http://dx.doi.org/10.1186/s12929-019-0609-7] [PMID: 31906949]
[47]
Schrimpf MR, Sippy KB, Briggs CA, et al. SAR of α7 nicotinic receptor agonists derived from tilorone: exploration of a novel nicotinic pharmacophore. Bioorg Med Chem Lett 2012; 22(4): 1633-8.
[http://dx.doi.org/10.1016/j.bmcl.2011.12.126] [PMID: 22281189]
[48]
Suresh A, Hung A. Molecular simulation study of the unbinding of α-conotoxin [ϒ4E]GID at the α7 and α4β2 neuronal nicotinic acetylcholine receptors. J Mol Graph Model 2016; 70: 109-21.
[http://dx.doi.org/10.1016/j.jmgm.2016.09.006] [PMID: 27721068]
[49]
Wang J, Kuryatov A, Sriram A, et al. An accessory agonist binding site promotes activation of α4β2* nicotinic acetylcholine receptors. J Biol Chem 2015; 290(22): 13907-18.
[http://dx.doi.org/10.1074/jbc.M115.646786] [PMID: 25869137]
[50]
Grupe M, Grunnet M, Bastlund JF, Jensen AA. Targeting α4β2 nicotinic acetylcholine receptors in central nervous system disorders: perspectives on positive allosteric modulation as a therapeutic approach. Basic Clin Pharmacol Toxicol 2015; 116(3): 187-200.
[http://dx.doi.org/10.1111/bcpt.12361] [PMID: 25441336]
[51]
Grady SR, Salminen O, Laverty DC, et al. The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochem Pharmacol 2007; 74(8): 1235-46.
[http://dx.doi.org/10.1016/j.bcp.2007.07.032] [PMID: 17825262]
[52]
Brunzell DH, Stafford AM, Dixon CI. Nicotinic receptor contributions to smoking: insights from human studies and animal models. Curr Addict Rep 2015; 2(1): 33-46.
[http://dx.doi.org/10.1007/s40429-015-0042-2] [PMID: 26301171]
[53]
Morales-Perez CL, Noviello CM, Hibbs RE. X-ray structure of the human α4β2 nicotinic receptor. Nature 2016; 538(7625): 411-5.
[http://dx.doi.org/10.1038/nature19785] [PMID: 27698419]
[54]
Lenz RA, Pritchett YL, Berry SM, et al. Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease. Alzheimer Dis Assoc Disord 2015; 29(3): 192-9.
[http://dx.doi.org/10.1097/WAD.0000000000000093] [PMID: 25973909]
[55]
Posadas I, López-Hernández B, Ceña V. Nicotinic receptors in neurodegeneration. Curr Neuropharmacol 2013; 11(3): 298-314.
[http://dx.doi.org/10.2174/1570159X11311030005] [PMID: 24179465]
[56]
Faundez-Parraguez M, Farias-Rabelo N, Gonzalez-Gutierrez JP, et al. Neonicotinic analogues: selective antagonists for α4β2 nicotinic acetylcholine receptors. Bioorg Med Chem 2013; 21(10): 2687-94.
[http://dx.doi.org/10.1016/j.bmc.2013.03.024] [PMID: 23561269]
[57]
Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H. Implications of GABAergic neurotransmission in Alzheimer’s disease. Front Aging Neurosci 2016; 8: 31.
[http://dx.doi.org/10.3389/fnagi.2016.00031] [PMID: 26941642]
[58]
Mandal PK, Kansara K, Dabas A. The GABA-working memory relashionship in Alzheimer´s disease J Alz Dis Rep 2017; 1: 43-5.
[59]
Grill JD, Cummings JL. Novel targets for Alzheimer’s disease treatment. Expert Ver Neurother 2010; 10: 711-28.
[http://dx.doi.org/10.1586/ern.10.29]
[60]
Scimemi A. Structure, function, and plasticity of GABA transportes. Front Cell Neurosci 2014; 8: 1-14.
[http://dx.doi.org/10.3389/fncel.2014.00161]
[61]
Drott J, Desire L, Drouin D, Pando M, Haun F. Etazolate improves performance in a foraging and homing task in aged rats. Eur J Pharmacol 2010; 634(1-3): 95-100.
[http://dx.doi.org/10.1016/j.ejphar.2010.02.036] [PMID: 20223232]
[62]
Vellas B, Sol O, Snyder PJ, et al. EHT0202/002 study group. EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res 2011; 8(2): 203-12.
[http://dx.doi.org/10.2174/156720511795256053] [PMID: 21222604]
[63]
Valproate in Dementia (VALID) ClinicalTrials.gov Identifier: NCT00071721 2020.
[64]
Tariot PN, Schneider LS, Cummings J, et al. Alzheimer’s Disease Cooperative Study Group. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 2011; 68(8): 853-61.
[http://dx.doi.org/10.1001/archgenpsychiatry.2011.72] [PMID: 21810649]
[65]
Petersen JG, Sørensen T, Damgaard M, et al. Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABA(A) receptor agonists. Eur J Med Chem 2014; 84: 404-16.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.039] [PMID: 25038482]
[66]
Claeysen S, Bockaert J, Giannoni P. Serotonin: a new hope in Alzheimer’s disease? ACS Chem Neurosci 2015; 6(7): 940-3.
[http://dx.doi.org/10.1021/acschemneuro.5b00135] [PMID: 26011650]
[67]
Butzlaff M, Ponimaskin E. The role of serotoninreceptors in Alzheimer’s disease. Opera Med Physiol 2016; 2: 77-86.
[68]
Geldenhuys WJ, Van der Schyf CJ. Role of serotonin in Alzheimer’s disease: a new therapeutic target? CNS Drugs 2011; 25(9): 765-81.
[http://dx.doi.org/10.2165/11590190-000000000-00000] [PMID: 21870888]
[69]
Jayarajan P, Bhyrapuneni G, Mudigonda K, et al. SUVN-D4010, a potent and selective 5-HT4 receptor partial agonist: safety, tolerability and pharmacokinetics in humans. Alzheimers Dement 2016; 7: 823-4.
[http://dx.doi.org/10.1016/j.jalz.2016.06.1673]
[70]
Nirogi R, Mohammed AR, Shinde AK, et al. Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists. J Med Chem 2018; 61(11): 4993-5008.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00457] [PMID: 29763304]
[71]
Shen F, Smith JAM, Chang R, et al. 5-HT(4) receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing in vitro: A pharmacodynamic and pharmacokinetic assessment. Neuropharmacology 2011; 61(1-2): 69-79.
[http://dx.doi.org/10.1016/j.neuropharm.2011.02.026] [PMID: 21392515]
[72]
Sabbagh MN. Drug development for Alzheimer’s disease: where are we now and where are we headed? Am J Geriatr Pharmacother 2009; 7(3): 167-85.
[http://dx.doi.org/10.1016/j.amjopharm.2009.06.003] [PMID: 19616185]
[73]
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 2010; 9(7): 702-16.
[http://dx.doi.org/10.1016/S1474-4422(10)70119-8] [PMID: 20610346]
[74]
Vera G, Lagos CF, Almendras S, et al. Extended N-arylsulfonylindoles as 5-HT6 receptor antagonists: design, synthesis & biological evaluation. Molecules 2016; 21(8): 1-35.
[http://dx.doi.org/10.3390/molecules21081070] [PMID: 27537868]
[75]
Gallivan JP, Dougherty DA. Cation-pi interactions in structural biology. Proc Natl Acad Sci USA 1999; 96(17): 9459-64.
[http://dx.doi.org/10.1073/pnas.96.17.9459] [PMID: 10449714]
[76]
Mella J, Villegas F, Morales-Verdejo C, Lagos C, Recabarren-Gadajo G. Structure-activity relationships studies on weakly basic N-arylsuldonylindoles with an antagonistic profile in the 5-HT6 receptor. J Mol Struct 2017; 1139: 362-70.
[http://dx.doi.org/10.1016/j.molstruc.2017.03.067]
[77]
Naddafi F, Mirshafiey A. The neglected role of histamine in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2013; 28(4): 327-36.
[http://dx.doi.org/10.1177/1533317513488925] [PMID: 23677734]
[78]
Cummings J, Morstorf T, Lee G. Alzheimer’s drug-development pipeline: 2016. Alzheimers Dement (N Y) 2016; 2(4): 222-32.
[http://dx.doi.org/10.1016/j.trci.2016.07.001] [PMID: 29067309]
[79]
Vohora D, Bhowmik M. Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer’s disease, ADHD, schizophrenia, and drug abuse. Front Syst Neurosci 2012; 6: 72.
[http://dx.doi.org/10.3389/fnsys.2012.00072] [PMID: 23109919]
[80]
Hancock AA. The challenge of drug discovery of a GPCR target: analysis of preclinical pharmacology of histamine H3 antagonists/inverse agonists. Biochem Pharmacol 2006; 71(8): 1103-13.
[http://dx.doi.org/10.1016/j.bcp.2005.10.033] [PMID: 16513092]
[81]
Haig GM, Pritchett Y, Meier A, et al. A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer’s dementia. J Alzheimers Dis 2014; 42(3): 959-71.
[http://dx.doi.org/10.3233/JAD-140291] [PMID: 25024314]
[82]
Wingen K, Stark H. Scaffold variations in amine warhead of histamine H3 receptor antagonists Drug Discov Today. Tech 2013; 10: 483-9.
[83]
Łazewska D, Kuder K, Ligneau X, et al. Piperidine variations in search for non-imidazole histamine H(3) receptor ligands. Bioorg Med Chem 2008; 16(18): 8729-36.
[http://dx.doi.org/10.1016/j.bmc.2008.07.071] [PMID: 18774720]
[84]
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): 832-44.
[http://dx.doi.org/10.1021/cn3000907] [PMID: 23173065]
[85]
Heckman PRA, Wouters C, Prickaerts J. Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer’s disease: a translational overview. Curr Pharm Des 2015; 21(3): 317-31.
[http://dx.doi.org/10.2174/1381612820666140826114601] [PMID: 25159073]
[86]
Ricciarelli R, Fedele E. Phosphodiesterase 4D: an enzyme to remember. Br J Pharmacol 2015; 172(20): 4785-9.
[http://dx.doi.org/10.1111/bph.13257] [PMID: 26211680]
[87]
Gallant M, Aspiotis R, Day S, et al. Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment. Bioorg Med Chem Lett 2010; 20(22): 6387-93.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.087] [PMID: 20933411]
[88]
Prickaerts J, Heckman PRA, Blokland A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert Opin Investig Drugs 2017; 26(9): 1033-48.
[http://dx.doi.org/10.1080/13543784.2017.1364360] [PMID: 28772081]
[89]
Peters M, Bletsch M, Stanley J, Wheeler D, Scott R, Tully T. The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice. Neuropsychopharmacology 2014; 39(13): 2938-48.
[http://dx.doi.org/10.1038/npp.2014.154] [PMID: 24964813]
[90]
Wang Z, Wang Y, Wang B, Li W, Huang L, Li X. Design, synthesis and evaluation of orally available clioquinol-moracin M hybrids as multi-target-directed ligands for cognitive improvement in a rat model of neurodegeneration in Alzheimer’s disease. J Med Chem 2015; 58(21): 8616-37.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01222] [PMID: 26473791]
[91]
Duce JA, Bush AI. Biological metals and Alzheimer’s disease: implications for therapeutics and diagnostics. Prog Neurobiol 2010; 92(1): 1-18.
[http://dx.doi.org/10.1016/j.pneurobio.2010.04.003] [PMID: 20444428]
[92]
Ishii M, Iadecola C. Metabolic and non-cognitive manifestations of Alzheimer’s disease: the hypothalamus as both culprit and target of pathology. Cell Metab 2015; 22(5): 761-76.
[http://dx.doi.org/10.1016/j.cmet.2015.08.016] [PMID: 26365177]
[93]
Mushtaq G, Khan JA, Kamal MA. Impaired glucose metabolism in Alzheimer’s disease and diabetes Enz Eng 2015; 4: 1-4.
[94]
Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) 2009; 6: 31.
[http://dx.doi.org/10.1186/1743-7075-6-31] [PMID: 19664276]
[95]
Costantini LC, Barr LJ, Vogel JL, Henderson ST. Hypometabolism as a therapeutic target in Alzheimer'sdisease BMC Nurosc 2008; 9: 1-9.
[96]
Miller BW, Willett KC, Desilets AR. Rosiglitazone and pioglitazone for the treatment of Alzheimer’s disease. Ann Pharmacother 2011; 45(11): 1416-24.
[http://dx.doi.org/10.1345/aph.1Q238] [PMID: 22028424]
[97]
Diniz LP, Tortelli V, Matias I, et al. Astrocyte transforming growth factor beta 1 protects synapses against Aβ oligomers in Alzheimer’s disease model. J Neurosci 2017; 37(28): 6797-809.
[http://dx.doi.org/10.1523/JNEUROSCI.3351-16.2017] [PMID: 28607171]
[98]
Schwartz M, Peralta Ramos JM, Ben-Yehuda H. A 20-year journey from axonal injury to neurodegenerative diseases and the prospect of immunotherapy for combating alzheimer’s disease. J Immunol 2020; 204(2): 243-50.
[http://dx.doi.org/10.4049/jimmunol.1900844] [PMID: 31907265]
[99]
Liu YH, Zeng F, Wang YR, et al. Immunity and Alzheimer’s disease: immunological perspectives on the development of novel therapies. Drug Discov Today 2013; 18(23-24): 1212-20.
[http://dx.doi.org/10.1016/j.drudis.2013.07.020] [PMID: 23954180]
[100]
Jevtic S, Sengar AS, Salter MW, McLaurin J. The role of the immune system in Alzheimer disease: Etiology and treatment. Ageing Res Rev 2017; 40: 84-94.
[http://dx.doi.org/10.1016/j.arr.2017.08.005] [PMID: 28941639]
[101]
De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell 2016; 164(4): 603-15.
[http://dx.doi.org/10.1016/j.cell.2015.12.056] [PMID: 26871627]
[102]
Su F, Bai F, Zhou H, Zhang Z. Microglial toll-like receptors and Alzheimer’s disease. Brain Behav Immun 2016; 52: 187-98.
[http://dx.doi.org/10.1016/j.bbi.2015.10.010] [PMID: 26526648]
[103]
https://investors.biogen.com/news-releases/news-release-details/biogen-plans-regulatory-filing-aducanumab-alzheimers-disease2020
[104]
Goure WF, Krafft GA, Jerecic J, Hefti F. Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res Ther 2014; 6(4): 42.
[http://dx.doi.org/10.1186/alzrt272] [PMID: 25045405]
[105]
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618): 50-6.
[http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]
[106]
Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N Engl J Med 2018; 378(4): 321-30.
[http://dx.doi.org/10.1056/NEJMoa1705971] [PMID: 29365294]
[107]
https://investor.lilly.com/news-releases/news-release-details/lilly-announces-topline-results-solanezumab-dominantly-inherited2020
[108]
U.S. Food & Drug Administration Department of Health and Human Services.. https://www.fda.gov/2018
[109]
Ivleva EA, Klimoichkin YN. Convenient synthesis of memantine hydrochloride. Org Prep Proced Int 2017; 49: 155-62.
[http://dx.doi.org/10.1080/00304948.2017.1291004]
[110]
Rawat AS, Pande S, Bhatt N, Kharatkar R, Belwal C, Vardhan A. Synthesis of donepezil hydrochloride via chemoselective hydrogenation. Org Process Res Dev 2013; 10: 1-5.
[http://dx.doi.org/10.1021/op400007p]
[111]
Li M, Zheng C, Kawada T, et al. Donepezil markedly improves long-term survival in rats with chronic heart failure after extensive myocardial infarction. Circ J 2013; 77(10): 2519-25.
[http://dx.doi.org/10.1253/circj.CJ-13-0476] [PMID: 23832513]
[112]
Foster PS, Drago V, Roosa KM, Campbell RW, Witt JC, Heilman KM. Donepezil versus Rivastigmine in patients with Alzheimer’s disease: attention and working memory. Alz Neurodegener Dis 2016; 2: 1-5.
[http://dx.doi.org/10.24966/AND-9608/100002]
[113]
Onor ML, Trevisiol M, Aguglia E. Rivastigmine in the treatment of Alzheimer’s disease: an update. Clin Interv Aging 2007; 2(1): 17-32.
[http://dx.doi.org/10.2147/ciia.2007.2.1.17] [PMID: 18044073]
[114]
Adler G, Mueller B, Articus K. The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer’s disease under daily practice conditions. Int J Clin Pract 2014; 68(4): 465-70.
[http://dx.doi.org/10.1111/ijcp.12374] [PMID: 24588972]
[115]
Yan P, Zhu G, Xie J, et al. Industrial Scale-up of enantioselective hydrogenation for the asymmetric synthesis of Rivastigmine. Org Process Res Dev 2012; 17: 307-12.
[http://dx.doi.org/10.1021/op3003147]
[116]
Ng YP, Or TC, Ip NY. Plant alkaloids as drug leads for Alzheimer’s disease. Neurochem Int 2015; 89: 260-70.
[http://dx.doi.org/10.1016/j.neuint.2015.07.018] [PMID: 26220901]
[117]
Baakman AC, ’t Hart E, Kay DG, et al. 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]
[118]
Marco-Contelles J, do Carmo Carreiras M, Rodríguez C, Villarroya M, García AG. Synthesis and pharmacology of galantamine. Chem Rev 2006; 106(1): 116-33.
[http://dx.doi.org/10.1021/cr040415t] [PMID: 16402773]
[119]
Rodrigues Simões MC, Dias Viegas FP, Moreira MS, et al. Donepezil: an important prototype to the design of new drug candidates for Alzheimer’s disease. Mini Rev Med Chem 2014; 14(1): 2-19.
[http://dx.doi.org/10.2174/1389557513666131119201353] [PMID: 24251806]
[120]
Silva MF, Dias KST, Gontijo VS, Ortiz CJC, Viegas-Jr C. Recent contributions of the Multi-Target Directed Ligands Approach in the Search for Effective Drugs Towards Alzheimer’s Disease. Curr Med Chem 2018; 12: 2-36.
[121]
Nesi G, Chen Q, Sestito S, et al. Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer’s disease. Eur J Med Chem 2017; 141: 232-9.
[http://dx.doi.org/10.1016/j.ejmech.2017.10.006] [PMID: 29031070]
[122]
Joubert J, Foka GB, Repsold BP, Oliver DW, Kapp E, Malan SF. Synthesis and evaluation of 7-substituted coumarin derivatives as multimodal monoamine oxidase-B and cholinesterase inhibitors for the treatment of Alzheimer’s disease. Eur J Med Chem 2017; 125: 853-64.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.041] [PMID: 27744252]
[123]
Li F, Wu JJ, Wang J, et al. Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer’s disease. Bioorg Med Chem 2017; 25(14): 3815-26.
[http://dx.doi.org/10.1016/j.bmc.2017.05.027] [PMID: 28549891]
[124]
Liu Z, Fang L, Zhang H, Gou S, Chen L. Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property. Bioorg Med Chem 2017; 25(8): 2387-98.
[http://dx.doi.org/10.1016/j.bmc.2017.02.049] [PMID: 28302511]
[125]
Eghtedari M, Sarrafi Y, Nadri H, et al. New tacrine-derived AChE/BuChE inhibitors: Synthesis and biological evaluation of 5-amino-2-phenyl-4H-pyrano[2,3-b]quinoline-3-carboxylates. Eur J Med Chem 2017; 128: 237-46.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.042] [PMID: 28189905]
[126]
Jalili-Baleh L, Nadri H, Moradi A, et al. New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer’s disease. Eur J Med Chem 2017; 139: 280-9.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.072] [PMID: 28803044]
[127]
Roldán-Peña JM, Alejandre-Ramos D, López Ó, et al. New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer’s and antiproliferative agents. Eur J Med Chem 2017; 138: 761-73.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.048] [PMID: 28728108]
[128]
Gazova Z, Soukup O, Sepsova V, et al. Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer’s disease treatment. Biochim Biophys Acta Mol Basis Dis 2017; 1863(2): 607-19.
[http://dx.doi.org/10.1016/j.bbadis.2016.11.020] [PMID: 27865910]
[129]
Yang X, Qiang X, Li Y, et al. Pyridoxine-resveratrol hybrids Mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer’s disease. Bioorg Chem 2017; 71: 305-14.
[http://dx.doi.org/10.1016/j.bioorg.2017.02.016] [PMID: 28267984]
[130]
Wang J, Cai P, Yang XL, et al. Novel cinnamamide-dibenzylamine hybrids: Potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer’s disease. Eur J Med Chem 2017; 139: 68-83.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.077] [PMID: 28800459]
[131]
Xu P, Zhang M, Sheng R, Ma Y. Synthesis and biological evaluation of deferiprone-resveratrol hybrids as antioxidants, Aβ1-42 aggregation inhibitors and metal-chelating agents for Alzheimer’s disease. Eur J Med Chem 2017; 127: 174-86.
[http://dx.doi.org/10.1016/j.ejmech.2016.12.045] [PMID: 28061347]
[132]
Reddy EK, Remya C, Mantosh K, et al. Novel tacrine derivatives exhibiting improved acetylcholinesterase inhibition: Design, synthesis and biological evaluation. Eur J Med Chem 2017; 139: 367-77.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.013] [PMID: 28810188]
[133]
Lan JS, Liu Y, Hou JW, et al. Design, synthesis and evaluation of resveratrol-indazole hybrids as novel monoamine oxidases inhibitors with amyloid-β aggregation inhibition. Bioorg Chem 2018; 76: 130-9.
[http://dx.doi.org/10.1016/j.bioorg.2017.11.009] [PMID: 29172101]
[134]
Xia CL, Wang N, Guo QL, et al. Design, synthesis and evaluation of 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for Alzheimer’s disease treatment. Eur J Med Chem 2017; 130: 139-53.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.042] [PMID: 28242549]
[135]
Luo L, Li Y, Qiang X, et al. Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease. Bioorg Med Chem 2017; 25(6): 1997-2009.
[http://dx.doi.org/10.1016/j.bmc.2017.02.027] [PMID: 28237559]
[136]
Zhao XJ, Gong DM, Jiang YR, Guo D, Zhu Y, Deng YC. Multipotent AChE and BACE-1 inhibitors for the treatment of Alzheimer’s disease: Design, synthesis and bio-analysis of 7-amino-1,4-dihydro-2H-isoquilin-3-one derivates. Eur J Med Chem 2017; 138: 738-47.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.006] [PMID: 28728106]
[137]
Sang Z, Wang K, Wang H, et al. Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 2017; 27(22): 5053-9.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.055] [PMID: 29033232]
[138]
Czarnecka K, Chufarova N, Halczuk K, et al. Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer’s disease treatment. Eur J Med Chem 2018; 145: 760-9.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.014] [PMID: 29353726]
[139]
Xiao G, Li Y, Qiang X, et al. Design, synthesis and biological evaluation of 4′-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 2017; 25(3): 1030-41.
[http://dx.doi.org/10.1016/j.bmc.2016.12.013] [PMID: 28011206]
[140]
Palanimuthu D, Poon R, Sahni S, et al. A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer’s disease. Eur J Med Chem 2017; 139: 612-32.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.021] [PMID: 28841514]
[141]
Dgachi Y, Sokolov O, Luzet V, et al. Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer’s disease therapy. Eur J Med Chem 2017; 126: 576-89.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.050] [PMID: 27918993]
[142]
Li Y, Qiang X, Luo L, et al. Multitarget drug design strategy against Alzheimer’s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties. Bioorg Med Chem 2017; 25(2): 714-26.
[http://dx.doi.org/10.1016/j.bmc.2016.11.048] [PMID: 27923535]
[143]
Ma F, Du H. Novel deoxyvasicinone derivatives as potent multitarget-directed ligands for the treatment of Alzheimer’s disease: Design, synthesis, and biological evaluation. Eur J Med Chem 2017; 140: 118-27.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.008] [PMID: 28923380]
[144]
Singh M, Kaur M, Singh N, Silakari O. Exploration of multi-target potential of chromen-4-one based compounds in Alzheimer’s disease: Design, synthesis and biological evaluations. Bioorg Med Chem 2017; 25(24): 6273-85.
[http://dx.doi.org/10.1016/j.bmc.2017.09.012] [PMID: 29089261]
[145]
Dias Viegas FP, de Freitas Silva M, Divino da Rocha M, et al. Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates. Eur J Med Chem 2018; 147: 48-65.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.066] [PMID: 29421570]
[146]
Xu YX, Wang H, Li XK, et al. Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 2018; 143: 33-47.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.025] [PMID: 29172081]
[147]
Qiang X, Li Y, Yang X, et al. DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimer’s therapy. Bioorg Med Chem Lett 2017; 27(4): 718-22.
[http://dx.doi.org/10.1016/j.bmcl.2017.01.050] [PMID: 28131710]

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