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Volume 24, Issue 28
  • ISSN: 1568-0266
  • E-ISSN: 1873-4294

Abstract

Alzheimer’s disease is a multifaceted neurodegenerative disease. Cholinergic dysfunction, amyloid β toxicity, tauopathies, oxidative stress, neuroinflammation are among the main pathologies of the disease. Ligands targeting more than one pathology, multi-target directed ligands, attract attention in the recent years to tackle Alzheimer’s disease. In this review, we aimed to cover different biochemical pathways, that are revealed in recent years for the pathology of the disease, as druggable targets such as cannabinoid receptors, matrix metalloproteinases, histone deacetylase and various kinases including, glycogen synthase kinase-3, mitogen-activated protein kinase and c-Jun N-terminal kinase, and their ligands for the treatment of Alzheimer’s disease in the hope of providing more realistic insights into the field.

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2024-01-01
2024-11-21

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References

  1. ScheltensP. De StrooperB. KivipeltoM. HolstegeH. ChételatG. TeunissenC.E. CummingsJ. van der FlierW.M. Alzheimer’s disease.Lancet2021397102841577159010.1016/S0140‑6736(20)32205‑4
     [Google Scholar]
  2. PattersonC. World Alzheimer Report 2018.The state of the art of dementia research: New frontiersAlzheimer’s Disease International.2018
     [Google Scholar]
  3. CummingsJ. LeeG. NahedP. KambarM.E.Z.N. ZhongK. FonsecaJ. TaghvaK. Alzheimer’s disease drug development pipeline: 2022.Alzheimers Dement.202281e1229510.1002/trc2.12295
     [Google Scholar]
  4. CummingsJ. LeeG. RitterA. SabbaghM. ZhongK. Alzheimer’s disease drug development pipeline: 2020.Alzheimers Dement.202061e1205010.1002/trc2.12050
     [Google Scholar]
  5. CummingsJ. LeeG. ZhongK. FonsecaJ. TaghvaK. Alzheimer’s disease drug development pipeline: 2021.Alzheimers Dement.202171e1217910.1002/trc2.12179
     [Google Scholar]
  6. CummingsJ. New approaches to symptomatic treatments for Alzheimer’s disease.Mol. Neurodegener.202116121310.1186/s13024‑021‑00424‑9
     [Google Scholar]
  7. OumataN. LuK. TengY. CavéC. PengY. GalonsH. RoquesB.P. Molecular mechanisms in Alzheimer’s disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules.Eur. J. Med. Chem.202224011457810.1016/j.ejmech.2022.114578
     [Google Scholar]
  8. scarpiniE. SchelternsP. FeldmanH. Treatment of Alzheimer’s disease; Current status and new perspectives.Lancet Neurol.20032953954710.1016/S1474‑4422(03)00502‑7
     [Google Scholar]
  9. GreigN.H. UtsukiT. YuQ.S. ZhuX. HollowayH.W. PerryT. LeeB. IngramD.K. LahiriD.K. A new therapeutic target in alzheimer’s disease treatment: Attention to butyrylcholinesterase.Curr. Med. Res. Opin.200117315916510.1185/03007990152673800
     [Google Scholar]
  10. GuillozetA.L. MesulamM.M. SmileyJ.F. MashD.C. Butyrylcholinesterase in the life cycle of amyloid plaques.Ann. Neurol.199742690991810.1002/ana.410420613
     [Google Scholar]
  11. HardyJ. SelkoeD.J. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics.Science2002297558035335610.1126/science.1072994
     [Google Scholar]
  12. MorphyR. RankovicZ. Designed multiple ligands. An emerging drug discovery paradigm.J. Med. Chem.200548216523654310.1021/jm058225d
     [Google Scholar]
  13. BennettD.A. SchneiderJ.A. WilsonR.S. BieniasJ.L. ArnoldS.E. Neurofibrillary tangles mediate the association of amyloid load with clinical alzheimer disease and level of cognitive function.Arch Neurol200461378384
     [Google Scholar]
  14. LewisJ. DicksonD.W. LinW.-L. ChisholmL. CorralA. JonesG. YenS.-H. SaharaN. SkipperL. YagerD. EckmanC. HardyJ. HuttonM. McGowanE. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science200129355341487149110.1126/science.1058189
     [Google Scholar]
  15. CavalliA. BolognesiM.L. MinariniA. RosiniM. TumiattiV. RecanatiniM. MelchiorreC. Multi-target-directed ligands to combat neurodegenerative diseases.J. Med. Chem.200851334737210.1021/jm7009364
     [Google Scholar]
  16. LalutJ. RochaisC. DallemagneP. Multiple ligands in neurodegenerative diseases.Drug Selectivity: An Evolving Concept in Medicinal ChemistryWiley Online Library201747750810.1002/9783527674381.ch16
     [Google Scholar]
  17. RaiS.N. SinghC. SinghA. SinghM.P. SinghB.K. Mitochondrial dysfunction: A potential therapeutic target to treat alzheimer’s disease.Mol. Neurobiol.20205773075308810.1007/s12035‑020‑01945‑y
     [Google Scholar]
  18. KeppK.P. Bioinorganic chemistry of alzheimer’s disease.Chem Rev20121125193523910.1021/cr300009x
     [Google Scholar]
  19. AlbertiniC. SalernoA. de Sena Murteira PinheiroP. BolognesiM.L. From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology.Med. Res. Rev.20214152606263310.1002/med.21699
     [Google Scholar]
  20. LemboV. BottegoniG. Systematic investigation of dual-target-directed ligands.J. Med. Chem.20246712103741038510.1021/acs.jmedchem.4c00838
     [Google Scholar]
  21. DeckerM. Design of Hybrid Molecules for Drug Development.Elsevier2017
     [Google Scholar]
  22. HowlettA.C. BreivogelC.S. ChildersS.R. DeadwylerS.A. HampsonR.E. PorrinoL.J. Cannabinoid physiology and pharmacology: 30 years of progress.Neuropharmacology20044734535810.1016/j.neuropharm.2004.07.030
     [Google Scholar]
  23. TurcotteC. BlanchetM.R. LavioletteM. FlamandN. The CB2 receptor and its role as a regulator of inflammation.Cell. Mol. Life Sci.201673234449447010.1007/s00018‑016‑2300‑4
     [Google Scholar]
  24. CabralG.A. Griffin-ThomasL. Emerging role of the cannabinoid receptor CB 2 in immune regulation: Therapeutic prospects for neuroinflammation.Expert Rev. Mol. Med.200911e310.1017/S1462399409000957
     [Google Scholar]
  25. McGeerP.L. McGeerE. Conquering alzheimer’s disease by self treatment.J. Alzheimers Dis.201864S361S36310.3233/JAD‑179913
     [Google Scholar]
  26. CassanoT. CalcagniniS. PaceL. De MarcoF. RomanoA. GaetaniS. Cannabinoid receptor 2 signaling in neurodegenerative disorders: From pathogenesis to a promising therapeutic target.Front. Neurosci.20171110.3389/fnins.2017.00030
     [Google Scholar]
  27. AsoE. FerrerI. CB2 cannabinoid receptor as potential target against alzheimer’s disease.Front. Neurosci.20161010.3389/fnins.2016.00243
     [Google Scholar]
  28. AsoE. FerrerI. Cannabinoids for treatment of Alzheimer’s disease: Moving toward the clinic.Front. Pharmacol.2014510.3389/fphar.2014.00037
     [Google Scholar]
  29. WuJ. BieB. YangH. XuJ.J. BrownD.L. NaguibM. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency.Neurobiol. Aging201334379180410.1016/j.neurobiolaging.2012.06.011
     [Google Scholar]
  30. FerrisiR. CeniC. BertiniS. MacchiaM. ManeraC. GadoF. Medicinal chemistry approach, pharmacology and neuroprotective benefits of CB2R modulators in neurodegenerative diseases.Pharmacol. Res.202117010560710.1016/j.phrs.2021.105607
     [Google Scholar]
  31. Gonzalez-NaranjoP. Multitarget cannabinoids as novel strategy for Alzheimer disease.Curr. Alzheimer Res.201310322923910.2174/1567205011310030002
     [Google Scholar]
  32. González-NaranjoP. Pérez-MaciasN. CampilloN.E. PérezC. AránV.J. GirónR. Sánchez-RoblesE. MartínM.I. Gómez-CañasM. García-ArencibiaM. Fernández-RuizJ. PáezJ.A. Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer’s disease.Eur. J. Med. Chem.201473567210.1016/j.ejmech.2013.11.026
     [Google Scholar]
  33. González-NaranjoP. Pérez-MaciasN. PérezC. RocaC. VacaG. GirónR. Sánchez-RoblesE. Martín-FontellesM.I. de CeballosM.L. Martin-RequeroA. CampilloN.E. PáezJ.A. Indazolylketones as new multitarget cannabinoid drugs.Eur. J. Med. Chem.20191669010710.1016/j.ejmech.2019.01.030
     [Google Scholar]
  34. Nuñez-BorqueE. González-NaranjoP. BartoloméF. AlquézarC. Reinares-SebastiánA. PérezC. CeballosM.L. PáezJ.A. CampilloN.E. Martín-RequeroÁ. Targeting cannabinoid receptor activation and BACE-1 activity counteracts TgAPP mice memory impairment and alzheimer’s disease lymphoblast alterations.Mol. Neurobiol.20205741938195110.1007/s12035‑019‑01813‑4
     [Google Scholar]
  35. MontanariS. MahmoudA.M. PruccoliL. RabbitoA. NaldiM. PetrallaS. MoraledaI. BartoliniM. MontiB. IriepaI. BellutiF. GobbiS. Di MarzoV. BisiA. TarozziA. LigrestiA. RampaA. Discovery of novel benzofuran-based compounds with neuroprotective and immunomodulatory properties for Alzheimer’s disease treatment.Eur. J. Med. Chem.201917824325810.1016/j.ejmech.2019.05.080
     [Google Scholar]
  36. PagéD. BalauxE. BoisvertL. LiuZ. MilburnC. TremblayM. WeiZ. WooS. LuoX. ChengY.X. YangH. SrivastavaS. ZhouF. BrownW. TomaszewskiM. WalpoleC. HodzicL. St-OngeS. GodboutC. SaloisD. PayzaK. Novel benzimidazole derivatives as selective CB2 agonists.Bioorg. Med. Chem. Lett.200818133695370010.1016/j.bmcl.2008.05.073
     [Google Scholar]
  37. DollesD. HoffmannM. GuneschS. MarinelliO. MöllerJ. SantoniG. ChatonnetA. LohseM.J. WittmannH.J. StrasserA. NabissiM. MauriceT. DeckerM. Structure–activity relationships and computational investigations into the development of potent and balanced dual-acting butyrylcholinesterase inhibitors and human cannabinoid receptor 2 ligands with pro-cognitive in vivo profiles.J. Med. Chem.20186141646166310.1021/acs.jmedchem.7b01760
     [Google Scholar]
  38. ScheinerM. DollesD. GuneschS. HoffmannM. NabissiM. MarinelliO. NaldiM. BartoliniM. PetrallaS. PoetaE. MontiB. FalkeisC. ViethM. HübnerH. GmeinerP. MaitraR. MauriceT. DeckerM. Dual-acting cholinesterase–human cannabinoid receptor 2 ligands show pronounced neuroprotection in vitro and overadditive and disease-modifying neuroprotective effects in vivo.J. Med. Chem.201962209078910210.1021/acs.jmedchem.9b00623
     [Google Scholar]
  39. SpatzP. SteinmüllerS.A.M. TutovA. PoetaE. MorilleauA. CarlesA. DeventerM.H. HofmannJ. StoveC.P. MontiB. MauriceT. DeckerM. Dual-acting small molecules: Subtype-selective cannabinoid receptor 2 agonist/butyrylcholinesterase inhibitor hybrids show neuroprotection in an alzheimer’s disease mouse model.J. Med. Chem.20236696414643510.1021/acs.jmedchem.3c00541
     [Google Scholar]
  40. JaneroD.R. MakriyannisA. Cannabinoid receptor antagonists: Pharmacological opportunities, clinical experience, and translational prognosis.Expert Opin. Emerg. Drugs2009141436510.1517/14728210902736568
     [Google Scholar]
  41. MugnainiC. RabbitoA. BrizziA. PalombiN. PetrosinoS. VerdeR. Di MarzoV. LigrestiA. CorelliF. Synthesis of novel 2-(1-adamantanylcarboxamido)thiophene derivatives. Selective cannabinoid type 2 (CB2) receptor agonists as potential agents for the treatment of skin inflammatory disease.Eur. J. Med. Chem.201916123925110.1016/j.ejmech.2018.09.070
     [Google Scholar]
  42. MugnainiC. BrizziA. PaolinoM. ScarselliE. CastelliR. de CandiaM. GambacortaN. NicolottiO. KostrzewaM. KumarP. MahmoudA.M. BorgonettiV. IannottaM. MoraceA. GaleottiN. MaioneS. AltomareC.D. LigrestiA. CorelliF. Novel dual-acting hybrids targeting type-2 cannabinoid receptors and cholinesterase activity show neuroprotective effects in vitro and amelioration of cognitive impairment in vivo.ACS Chem. Neurosci.202415595597110.1021/acschemneuro.3c00656
     [Google Scholar]
  43. ZipfelP. RochaisC. BarangerK. RiveraS. DallemagneP. Matrix metalloproteinases as new targets in alzheimer’s disease: Opportunities and challenges.J. Med. Chem.20206319107051072510.1021/acs.jmedchem.0c00352
     [Google Scholar]
  44. SternlichtM.D. WerbZ. How matrix metalloproteinases regulate cell behaviorAnnu Rev Cell Dev Biol200117463516
     [Google Scholar]
  45. Page-McCawA. EwaldA.J. WerbZ. Matrix metalloproteinases and the regulation of tissue remodelling.Nat. Rev. Mol. Cell Biol.20078322123310.1038/nrm2125
     [Google Scholar]
  46. BarangerK. RiveraS. LiechtiF.D. GrandgirardD. BigasJ. SecoJ. TarragoT. LeibS.L. KhrestchatiskyM. Endogenous and synthetic MMP inhibitors in CNS physiopathology.Prog Brain Res201421431335110.1016/B978‑0‑444‑63486‑3.00014‑1
     [Google Scholar]
  47. RiveraS. García-GonzálezL. KhrestchatiskyM. BarangerK. Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other neurodegenerative disorders.Cell. Mol. Life Sci.201976163167319110.1007/s00018‑019‑03178‑2
     [Google Scholar]
  48. RosenbergG.A. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases.Lancet Neurol.20098220521610.1016/S1474‑4422(09)70016‑X
     [Google Scholar]
  49. BehlT. KaurG. SehgalA. BhardwajS. SinghS. BuhasC. Judea-PustaC. UivarosanD. MunteanuM.A. BungauS. Multifaceted role of matrix metalloproteinases in neurodegenerative diseases: Pathophysiological and therapeutic perspectives.Int. J. Mol. Sci.2021223141310.3390/ijms22031413
     [Google Scholar]
  50. PandaS.P. SoniU. A review of dementia, focusing on the distinct roles of viral protein corona and MMP9 in dementia: Potential pharmacotherapeutic priorities.Ageing Res. Rev.20227510156010.1016/j.arr.2022.101560
     [Google Scholar]
  51. PyN.A. BonnetA.E. BernardA. MarchalantY. CharratE. CheclerF. KhrestchatiskyM. BarangerK.Ã. RiveraS. Differential spatio-temporal regulation of MMPs in the 5xFAD mouse model of Alzheimer’s disease: Evidence for a pro-amyloidogenic role of MT1-MMP.Front. Aging Neurosci.2014610.3389/fnagi.2014.00247
     [Google Scholar]
  52. BackstromJ.R. LimG.P. CullenM.J. Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40).J Neurosci1996162479107919
     [Google Scholar]
  53. YanP. HuX. SongH. YinK. BatemanR.J. CirritoJ.R. XiaoQ. HsuF.F. TurkJ.W. XuJ. HsuC.Y. HoltzmanD.M. LeeJ.M. Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ.J. Biol. Chem.200628134245662457410.1074/jbc.M602440200
     [Google Scholar]
  54. LlanoE. PendásA.M. FreijeJ.M. KnauperV. Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase A overexpressed in brain tumors.Cancer Res1999591125702576
     [Google Scholar]
  55. PeiD. Identification and characterization of the fifth membrane- type matrix metalloproteinase MT5-MMP.J Biol Chem1999274138925893210.1074/jbc.274.13.8925
     [Google Scholar]
  56. LiK. TayF.R. YiuC.K.Y. The past, present and future perspectives of matrix metalloproteinase inhibitors.Pharmacol. Ther.202020710746510.1016/j.pharmthera.2019.107465
     [Google Scholar]
  57. KumarD. GuptaS.K. GaneshpurkarA. GuttiG. KrishnamurthyS. ModiG. SinghS.K. Development of Piperazinediones as dual inhibitor for treatment of Alzheimer’s disease.Eur. J. Med. Chem.20181508710110.1016/j.ejmech.2018.02.078
     [Google Scholar]
  58. SwethaR. KumarD. GuptaS.K. GaneshpurkarA. SinghR. GuttiG. KumarD. JanaS. KrishnamurthyS. SinghS.K. Multifunctional hybrid sulfonamides as novel therapeutic agents for Alzheimer’s disease.Future Med. Chem.201911243161317810.4155/fmc‑2019‑0106
     [Google Scholar]
  59. KumarD Development of Adamantyl Analogous as NMDA Receptor Antagonist for Treatment of AD2019
     [Google Scholar]
  60. BertranA. KhomiakD. KonopkaA. RejmakE. BulskaE. SecoJ. KaczmarekL. TarragóT. PradesR. Design and synthesis of selective and blood-brain barrier-permeable hydroxamate-based gelatinase inhibitors.Bioorg. Chem.20209410336510.1016/j.bioorg.2019.103365
     [Google Scholar]
  61. CicconeL. VandoorenJ. NencettiS. OrlandiniE. Natural marine and terrestrial compounds as modulators of matrix metalloproteinases-2 (MMP-2) and MMP-9 in alzheimer’s disease.Pharmaceuticals20211428610.3390/ph14020086
     [Google Scholar]
  62. IsholaA.A. AdewoleK.E. In silico screening of anticholinesterase alkaloids for cyclooxygenase-2 (COX-2) and matrix metalloproteinase 8 (MMP-8) inhibitory potentials as multi-target inhibitors of Alzheimer’s disease.Med. Chem. Res.201928101704171710.1007/s00044‑019‑02407‑4
     [Google Scholar]
  63. HanB. WangM. LiJ. ChenQ. SunN. YangX. ZhangQ. Perspectives and new aspects of histone deacetylase inhibitors in the therapy of CNS diseases.Eur. J. Med. Chem.202325811561310.1016/j.ejmech.2023.115613
     [Google Scholar]
  64. StünkelW. CampbellR.M. Sirtuin 1 (SIRT1): The misunderstood HDAC.SLAS Discov.201116101153116910.1177/1087057111422103
     [Google Scholar]
  65. LoPrestiP. Hdac6 in diseases of cognition and of neurons.Cells20201011210.3390/cells10010012
     [Google Scholar]
  66. LiT. ZhangC. HassanS. LiuX. SongF. ChenK. ZhangW. YangJ. Histone deacetylase 6 in cancer.J. Hematol. Oncol.201811111110.1186/s13045‑018‑0654‑9
     [Google Scholar]
  67. LatchevaN.K. ViveirosJ.M. WaddellE.A. NguyenP.T.T. LieblF.L.W. MarendaD.R. Epigenetic crosstalk: Pharmacological inhibition of HDACs can rescue defective synaptic morphology and neurotransmission phenotypes associated with loss of the chromatin reader Kismet.Mol. Cell. Neurosci.201887778510.1016/j.mcn.2017.11.007
     [Google Scholar]
  68. XuK. DaiX.L. HuangH.C. JiangZ.F. Targeting HDACs: A promising therapy for Alzheimer’s disease.Oxid. Med. Cell. Longev.201120111510.1155/2011/143269
     [Google Scholar]
  69. ZhangL. ShengS. QinC. The role of HDAC6 in alzheimer’s disease.J. Alzheimers Dis.20133328329510.3233/JAD‑2012‑120727
     [Google Scholar]
  70. JiaoF. GongZ. The beneficial roles of sirt1 in neuroinflammation-related diseases.Oxid Med Cell Longev2020202010.1155/2020/6782872
     [Google Scholar]
  71. ManalM. ChandrasekarM.J.N. Gomathi PriyaJ. NanjanM.J. Inhibitors of histone deacetylase as antitumor agents: A critical review.Bioorg. Chem.201667184210.1016/j.bioorg.2016.05.005
     [Google Scholar]
  72. GuoZ. ZhangZ. ZhangY. WangG. HuangZ. ZhangQ. LiJ. Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction.Eur. J. Med. Chem.202121811338310.1016/j.ejmech.2021.113383
     [Google Scholar]
  73. YuC.W. ChangP.T. HsinL.W. ChernJ.W. Quinazolin-4-one derivatives as selective histone deacetylase-6 inhibitors for the treatment of Alzheimer’s disease.J. Med. Chem.201356176775679110.1021/jm400564j
     [Google Scholar]
  74. TsengH.J. LinM.H. ShiaoY.J. YangY.C. ChuJ.C. ChenC.Y. ChenY.Y. LinT.E. SuC.J. PanS.L. ChenL.C. WangC.Y. HsuK.C. HuangW.J. Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease.Eur. J. Med. Chem.202019211219310.1016/j.ejmech.2020.112193
     [Google Scholar]
  75. HsuK.C. ChuJ.C. TsengH.J. LiuC.I. WangH.C. LinT.E. LeeH.S. HsinL.W. WangA.H.J. LinC.H. HuangW.J. Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors.Eur. J. Med. Chem.202121911341910.1016/j.ejmech.2021.113419
     [Google Scholar]
  76. ChenX. ChenX. SteimbachR.R. WuT. LiH. DanW. ShiP. CaoC. LiD. MillerA.K. QiuZ. GaoJ. ZhuY. Novel 2, 5-diketopiperazine derivatives as potent selective histone deacetylase 6 inhibitors: Rational design, synthesis and antiproliferative activity.Eur. J. Med. Chem.202018711195010.1016/j.ejmech.2019.111950
     [Google Scholar]
  77. LiangT. XieZ. DangB. WangJ. ZhangT. LuanX. LuT. CaoC. ChenX. Discovery of indole-piperazine derivatives as selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting activities and neuroprotective activities.Bioorg. Med. Chem. Lett.20238112914810.1016/j.bmcl.2023.129148
     [Google Scholar]
  78. HeF. RanY. LiX. WangD. ZhangQ. LvJ. YuC. QuY. ZhangX. XuA. WeiC. ChouC.J. WuJ. Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer’s disease.Bioorg. Chem.202010310410910.1016/j.bioorg.2020.104109
     [Google Scholar]
  79. YaoC. JiangX. ZhaoR. ZhongZ. GeJ. ZhuJ. YeX.Y. XieY. LiuZ. XieT. BaiR. HDAC1/MAO-B dual inhibitors against Alzheimer’s disease: Design, synthesis and biological evaluation of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids.Bioorg. Chem.202212210572410.1016/j.bioorg.2022.105724
     [Google Scholar]
  80. HangerD.P. AndertonB.H. NobleW. Tau phosphorylation: The therapeutic challenge for neurodegenerative disease.Trends Mol. Med.200915311211910.1016/j.molmed.2009.01.003
     [Google Scholar]
  81. ShiX.L. YanN. CuiY.J. LiuZ.P. A unique gsk-3β inhibitor b10 has a direct effect on aβ, targets tau and metal dyshomeostasis, and promotes neuronal neurite outgrowth.Cells20209364910.3390/cells9030649
     [Google Scholar]
  82. AlvarezA. ToroR. CáceresA. MaccioniR.B. Inhibition of tau phosphorylating protein kinase cdk5 prevents β-amyloid-induced neuronal death.FEBS Lett.1999459342142610.1016/S0014‑5793(99)01279‑X
     [Google Scholar]
  83. ThakurS. DhapolaR. SarmaP. MedhiB. ReddyD.H. Neuroinflammation in alzheimer’s disease: Current progress in molecular signaling and therapeutics.Inflammation202346111710.1007/s10753‑022‑01721‑1
     [Google Scholar]
  84. LeeJ.K. KimN.J. Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease.Molecules2017228128710.3390/molecules22081287
     [Google Scholar]
  85. ZhaoY. KucaK. WuW. WangX. NepovimovaE. MusilekK. WuQ. Hypothesis: JNK signaling is a therapeutic target of neurodegenerative diseases.Alzheimers Dement.202218115215810.1002/alz.12370
     [Google Scholar]
  86. WangC. CuiY. XuT. ZhouY. YangR. WangT. New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.Biochem. Pharmacol.202321811592310.1016/j.bcp.2023.115923
     [Google Scholar]
  87. WangY. TianQ. LiuE.J. ZhaoL. SongJ. LiuX.A. RenQ.G. JiangX. ZengJ. YangY.T. WangJ.Z. Activation of GSK-3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats.J. Cell. Mol. Med.201721123515352810.1111/jcmm.13262
     [Google Scholar]
  88. BradleyC.A. PeineauS. TaghibiglouC. NicolasC.S. WhitcombD.J. BortolottoZ.A. KaangB.K. ChoK. WangY.T. CollingridgeG.L. A pivotal role of GSK-3 in synaptic plasticity.Front. Mol. Neurosci.2012510.3389/fnmol.2012.00013
     [Google Scholar]
  89. LovestoneS. BoadaM. DuboisB. HüllM. RinneJ.O. HuppertzH.J. CaleroM. AndrésM.V. Gómez-CarrilloB. LeónT. del SerT. A phase II trial of tideglusib in alzheimer’s disease.J. Alzheimers Dis.2015451758810.3233/JAD‑141959
     [Google Scholar]
  90. ShriS.R. ManandharS. NayakY. PaiK.S.R. Role of GSK-3β inhibitors: New promises and opportunities for alzheimer’s disease.Adv. Pharm. Bull.202313468870010.34172/apb.2023.071
     [Google Scholar]
  91. ArfeenM. BhagatS. PatelR. PrasadS. RoyI. ChakrabortiA.K. BharatamP.V. Design, synthesis and biological evaluation of 5-benzylidene-2-iminothiazolidin-4-ones as selective GSK-3β inhibitors.Eur. J. Med. Chem.201612172773610.1016/j.ejmech.2016.04.075
     [Google Scholar]
  92. KhanfarM.A. HillR.A. KaddoumiA. El SayedK.A. Discovery of novel GSK-3β inhibitors with potent in vitro and in Vivo activities and excellent brain permeability using combined ligand- and structure-based virtual screening.J. Med. Chem.201053248534854510.1021/jm100941j
     [Google Scholar]
  93. PandeyM.K. DeGradoT.R. Glycogen synthase kinase-3 (GSK-3)-targeted therapy and imaging.Theranostics20166457159310.7150/thno.14334
     [Google Scholar]
  94. GuptaV. MahataT. RoyR. GharaiP.K. JanaA. GargS. GhoshS. Discovery of imidazole-based GSK-3β inhibitors for transdifferentiation of human mesenchymal stem cells to neurons: A potential single-molecule neurotherapeutic foresight.Front. Mol. Neurosci.202215100241910.3389/fnmol.2022.1002419
     [Google Scholar]
  95. Al-blewiF. ShaikhS.A. NaqviA. AljohaniF. AouadM.R. IhmaidS. RezkiN. Design and synthesis of novel imidazole derivatives possessing triazole pharmacophore with potent anticancer activity, and in silico ADMET with GSK-3β molecular docking investigations.Int. J. Mol. Sci.2021223116210.3390/ijms22031162
     [Google Scholar]
  96. DongY. LuJ. ZhangS. ChenL. WenJ. WangF. MaoY. LiL. ZhangJ. LiaoS. DongL. Design, synthesis and bioevaluation of 1,2,4-thiadiazolidine-3,5-dione derivatives as potential GSK-3β inhibitors for the treatment of Alzheimer’s disease.Bioorg. Chem.202313410644610.1016/j.bioorg.2023.106446
     [Google Scholar]
  97. LiuJ.G. ZhaoD. GongQ. BaoF. ChenW.W. ZhangH. XuM.H. Development of bisindole-substituted aminopyrazoles as novel gsk-3β inhibitors with suppressive effects against microglial inflammation and oxidative neurotoxicity.ACS Chem. Neurosci.202011203398340810.1021/acschemneuro.0c00520
     [Google Scholar]
  98. JiangX.Y. ChenT.K. ZhouJ.T. HeS.Y. YangH.Y. ChenY. QuW. FengF. SunH.P. Dual GSK-3β/AChE inhibitors as a new strategy for multitargeting anti-alzheimer’s disease drug discovery.ACS Med. Chem. Lett.20189317117610.1021/acsmedchemlett.7b00463
     [Google Scholar]
  99. JiangX. ZhouJ. WangY. ChenL. DuanY. HuangJ. LiuC. ChenY. LiuW. SunH. FengF. QuW. Rational design and biological evaluation of a new class of thiazolopyridyl tetrahydroacridines as cholinesterase and GSK-3 dual inhibitors for Alzheimer’s disease.Eur. J. Med. Chem.202020711275110.1016/j.ejmech.2020.112751
     [Google Scholar]
  100. JiangX. WangY. LiuC. XingC. WangY. LyuW. WangS. LiQ. ChenT. ChenY. FengF. LiuW. SunH. Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer’s disease.Bioorg. Med. Chem.20213011594010.1016/j.bmc.2020.115940
     [Google Scholar]
  101. YaoH. UrasG. ZhangP. XuS. YinY. LiuJ. QinS. LiX. AllenS. BaiR. GongQ. ZhangH. ZhuZ. XuJ. Discovery of novel tacrine–pyrimidone hybrids as potent dual AChE/GSK-3 inhibitors for the treatment of alzheimer’s disease.J. Med. Chem.202164117483750610.1021/acs.jmedchem.1c00160
     [Google Scholar]
  102. GandiniA. BartoliniM. TedescoD. Martinez-GonzalezL. RocaC. CampilloN.E. Zaldivar-DiezJ. PerezC. ZuccheriG. MitiA. FeoliA. CastellanoS. PetrallaS. MontiB. RossiM. ModaF. LegnameG. MartinezA. BolognesiM.L. Tau-centric multitarget approach for alzheimer’s disease: Development of first-in-class dual glycogen synthase kinase 3β and tau-aggregation inhibitors.J. Med. Chem.201861177640765610.1021/acs.jmedchem.8b00610
     [Google Scholar]
  103. SivaprakasamP. HanX. CivielloR.L. Jacutin-PorteS. KishK. PokrossM. LewisH.A. AhmedN. SzapielN. NewittJ.A. BaldwinE.T. XiaoH. KrauseC.M. ParkH. NophskerM. LippyJ.S. BurtonC.R. LangleyD.R. MacorJ.E. DubowchikG.M. Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core.Bioorg. Med. Chem. Lett.20152591856186310.1016/j.bmcl.2015.03.046
     [Google Scholar]
  104. HartzR.A. AhujaV.T. SivaprakasamP. XiaoH. KrauseC.M. ClarkeW.J. KishK. LewisH. SzapielN. RaviralaR. MutalikS. NakmodeD. ShahD. BurtonC.R. MacorJ.E. DubowchikG.M. Design, structure–activity relationships, and in vivo evaluation of potent and brain-penetrant imidazo[1,2- b ]pyridazines as glycogen synthase kinase-3β (GSK-3β) inhibitors.J. Med. Chem.20236664231425210.1021/acs.jmedchem.3c00133
     [Google Scholar]
  105. CorrêaS.A.L. EalesK.L. The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease.J. Signal Transduct.2012201211210.1155/2012/649079
     [Google Scholar]
  106. ZhangY.Y. MeiZ.Q. WuJ.W. WangZ.X. Enzymatic activity and substrate specificity of mitogen-activated protein kinase p38α in different phosphorylation states.J. Biol. Chem.200828339265912660110.1074/jbc.M801703200
     [Google Scholar]
  107. MunozL. AmmitA.J. Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease.Neuropharmacology201058356156810.1016/j.neuropharm.2009.11.010
     [Google Scholar]
  108. MaphisN. JiangS. XuG. Kokiko-CochranO.N. RoyS.M. Van EldikL.J. WattersonD.M. LambB.T. BhaskarK. Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology.Alzheimers Res. Ther.2016815410.1186/s13195‑016‑0221‑y
     [Google Scholar]
  109. ChenB. TengY. ZhangX. LvX. YinY. Metformin alleviated A β -induced apoptosis via the suppression of JNK MAPK signaling pathway in cultured hippocampal neurons.BioMed Res. Int.201620161810.1155/2016/1421430
     [Google Scholar]
  110. MunozL. RanaivoH.R. RoyS.M. HuW. CraftJ.M. McNamaraL.K. ChicoL.W. Van EldikL.J. WattersonD.M. A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model.J. Neuroinflammation2007412110.1186/1742‑2094‑4‑21
     [Google Scholar]
  111. RanaivoH.R. CraftJ.M. HuW. GuoL. WingL.K. Van EldikL.J. WattersonD.M. Glia as a therapeutic target: Selective suppression of human amyloid-β-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration.J. Neurosci.200626266267010.1523/JNEUROSCI.4652‑05.2006
     [Google Scholar]
  112. RoyS.M. Grum-TokarsV.L. SchavockyJ.P. SaeedF. StaniszewskiA. TeichA.F. ArancioO. BachstetterA.D. WebsterS.J. Van EldikL.J. MinasovG. AndersonW.F. PelletierJ.C. WattersonD.M. Targeting human central nervous system protein kinases: An isoform selective p38αmapk inhibitor that attenuates disease progression in alzheimer’s disease mouse models.ACS Chem. Neurosci.20156466668010.1021/acschemneuro.5b00002
     [Google Scholar]
  113. HeoJ. ShinH. LeeJ. KimT. InnK.S. KimN.J. Synthesis and biological evaluation of N-cyclopropylbenzamide-benzophenone hybrids as novel and selective p38 mitogen activated protein kinase (MAPK) inhibitors.Bioorg. Med. Chem. Lett.201525173694369810.1016/j.bmcl.2015.06.036
     [Google Scholar]
  114. GeeM.S. SonS.H. JeonS.H. DoJ. KimN. JuY.J. LeeS.J. ChungE.K. InnK.S. KimN.J. LeeJ.K. A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse.Alzheimers Res. Ther.20201214510.1186/s13195‑020‑00617‑2
     [Google Scholar]
  115. SpencerJ.P.E. The interactions of flavonoids within neuronal signalling pathways.Genes Nutr.20072325727310.1007/s12263‑007‑0056‑z
     [Google Scholar]
  116. CalderaroA. PatanèG.T. TelloneE. BarrecaD. FicarraS. MisitiF. LaganàG. The neuroprotective potentiality of flavonoids on alzheimer’s disease.Int. J. Mol. Sci.202223231483510.3390/ijms232314835
     [Google Scholar]
  117. LiuP. ZhouY. ShiJ. WangF. YangX. ZhengX. WangY. HeY. XieX. PangX. Myricetin improves pathological changes in 3×Tg-AD mice by regulating the mitochondria-NLRP3 inflammasome-microglia channel by targeting P38 MAPK signaling pathway.Phytomedicine202311515480110.1016/j.phymed.2023.154801
     [Google Scholar]
  118. AntoniouX. FalconiM. Di MarinoD. BorselloT. JNK3 as a therapeutic target for neurodegenerative diseases.J. Alzheimers Dis.20112463364210.3233/JAD‑2011‑091567
     [Google Scholar]
  119. WaetzigV. HerdegenT. Context-specific inhibition of JNKs: Overcoming the dilemma of protection and damage.Trends Pharmacol. Sci.20052645546110.1016/j.tips.2005.07.006
     [Google Scholar]
  120. WeiH. ZhangH. XieJ. MengD. WangX. KeD. ZengJ. LiuR. Protein phosphatase 2A as a drug target in the treatment of cancer and alzheimer’s disease.Curr. Med. Sci.20204011810.1007/s11596‑020‑2140‑1
     [Google Scholar]
  121. ArdanazC.G. EzkurdiaA. BejaranoA. EcharteB. SmerdouC. MartisovaE. Martínez-ValbuenaI. LuquinM.R. RamírezM.J. SolasM. JNK3 overexpression in the entorhinal cortex impacts on the hippocampus and induces cognitive deficiencies and tau misfolding.ACS Chem. Neurosci.202314112074208810.1021/acschemneuro.3c00092
     [Google Scholar]
  122. DouX. HuangH. LiY. JiangL. WangY. JinH. JiaoN. ZhangL. ZhangL. LiuZ. Multistage screening reveals 3-substituted indolin-2-one derivatives as novel and isoform-selective c-Jun N-terminal kinase 3 (JNK3) inhibitors: Implications to drug discovery for potential treatment of neurodegenerative diseases.J. Med. Chem.201962146645666410.1021/acs.jmedchem.9b00537
     [Google Scholar]
  123. LiZ. ZhuG. LiuX. GaoT. FangF. DouX. LiY. ZhengR. JinH. ZhangL. LiuZ. ZhangL. The structure-based optimization of 3-substituted indolin-2-one derivatives as potent and isoform-selective c-Jun N-terminal kinase 3 (JNK3) inhibitors and biological evaluation.Eur. J. Med. Chem.202325011516710.1016/j.ejmech.2023.115167
     [Google Scholar]
  124. DouX. HuangH. JiangL. ZhuG. JinH. JiaoN. ZhangL. LiuZ. ZhangL. Rational modification, synthesis and biological evaluation of 3,4-dihydroquinoxalin-2(1H)-one derivatives as potent and selective c-Jun N-terminal kinase 3 (JNK3) inhibitors.Eur. J. Med. Chem.202020111244510.1016/j.ejmech.2020.112445
     [Google Scholar]
  125. KimM. LeeJ. JungK. KimM. ParkY.J. AhnH. KwonY.H. HahJ.M. Syntheses and biological evaluation of 1-heteroaryl-2-aryl-1 H -benzimidazole derivatives as c-Jun N-terminal kinase inhibitors with neuroprotective effects.Bioorg. Med. Chem.20132182271228510.1016/j.bmc.2013.02.021
     [Google Scholar]
  126. JunJ. BaekJ. YangS. MoonH. KimH. ChoH. HahJ.M. Discovery of a potent and selective JNK3 inhibitor with neuroprotective effect against amyloid β-induced neurotoxicity in primary rat neurons.Int. J. Mol. Sci.202122201108410.3390/ijms222011084
     [Google Scholar]
  127. ZhengK. IqbalS. HernandezP. ParkH. LoGrassoP.V. FengY. Design and synthesis of highly potent and isoform selective JNK3 inhibitors: SAR studies on aminopyrazole derivatives.J. Med. Chem.20145723100131003010.1021/jm501256y
     [Google Scholar]
  128. FengY. ParkH. RyuJ.C. YoonS.O.K. N -aromatic-substituted indazole derivatives as brain-penetrant and orally bioavailable JNK3 inhibitors.ACS Med. Chem. Lett.202112101546155210.1021/acsmedchemlett.1c00334
     [Google Scholar]
  129. JunJ. MoonH. YangS. LeeJ. BaekJ. KimH. ChoH. HwangK. AhnS. KimY. KimG. KimH. KwonH. HahJ.M. Carbamate JNK3 inhibitors show promise as effective treatments for alzheimer’s disease: In vivo studies on mouse models.J. Med. Chem.20236696372639010.1021/acs.jmedchem.3c00393
     [Google Scholar]
  130. JunJ. YangS. LeeJ. MoonH. KimJ. JungH. ImD. OhY. JangM. ChoH. BaekJ. KimH. KangD. BaeH. TakC. HwangK. KwonH. KimH. HahJ.M. Discovery of novel imidazole chemotypes as isoform-selective JNK3 inhibitors for the treatment of Alzheimer’s disease.Eur. J. Med. Chem.202324511489410.1016/j.ejmech.2022.114894
     [Google Scholar]
  131. JunJ. BaekJ. KangD. MoonH. KimH. ChoH. HahJ.M. Novel 1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carboxamide-based JNK3 inhibitors: Design, synthesis, molecular docking, and therapeutic potential in neurodegenerative diseases.Eur. J. Med. Chem.202324511491710.1016/j.ejmech.2022.114917
     [Google Scholar]
/content/journals/ctmc/10.2174/0115680266318722240809050235
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Recent Molecular Targets and their Ligands for the Treatment of Alzheimer Disease
Curr. Top. Med. Chem. 24, 2447 (2024); https://doi.org/10.2174/0115680266318722240809050235
/content/journals/ctmc/10.2174/0115680266318722240809050235
/content/journals/ctmc/10.2174/0115680266318722240809050235
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  • Article Type:     Review Article
Keyword(s): Alzheimer’s disease; c-Jun N-terminal kinases; Cannabinoid receptors; Glycogen synthase kinase-3β; Histone deacetylases; Matrix metalloproteinases; Mitogen-activated protein kinases

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