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CC BY 4.0 · Pharmaceutical Fronts 2019; 01(01): e22-e32
DOI: 10.1055/s-0039-1698405
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Small-Molecule Amyloid Beta-Aggregation Inhibitors in Alzheimer's Disease Drug Development

Sharmin Reza Chowdhury
1   Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Fangzhou Xie
1   Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Jinxin Gu
1   Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Lei Fu
1   Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2019 (online)

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Abstract

Alzheimer's disease (AD) is still an incurable neurodegenerative disease that causes dementia. AD changes the brain function that, over time, impairs memory and diminishes judgment and reasoning ability. Pathophysiology of AD is complex. Till now the cause of AD remains unknown, but risk factors include family history and genetic predisposition. The drugs previously approved for AD treatment do not modify the disease process and only provide symptomatic improvement. Over the past few decades, research has led to significant progress in the understanding of the disease, leading to several novel strategies that may modify the disease process. One of the major developments in this direction is the amyloid β (Aβ) aggregation. Small molecules could block the initial stages of Aβ aggregation, which could be the starting point for the design and development of new AD drugs in the near future. In this review we summarize the most promising small-molecule Aβ-aggregation inhibitors including natural compounds, novel small molecules, and also those are in clinical trials. Moreover, we briefly summarized some reported docking studies of small-molecule Aβ aggregation inhibitors. These will give us an idea about the chemical features required to design novel small molecules with anti-Aβ aggregation properties.

Keywords

Alzheimer's disease - small molecule amyloid β-aggregation inhibitors - drug design
 

  • Reference

  • 1 Godyń J, Jończyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep 2016; 68 (01) 127-138
    CrossrefPubMedGoogle Scholar
  • 2 Baharloo F, Moslemin MH, Nadri H. , et al. Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors. Eur J Med Chem 2015; 93: 196-201
    CrossrefPubMedGoogle Scholar
  • 3 Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011; 7 (03) 137-152
    CrossrefPubMedGoogle Scholar
  • 4 Wimo A, Jönsson L, Bond J, Prince M, Winblad B. ; Alzheimer Disease International. The worldwide economic impact of dementia 2010. Alzheimers Dement 2013; 9 (01) 1.e3-11.e3
    Google Scholar
  • 5 Prince MJ, Acosta D, Castro-Costa E, Jackson J, Shaji KS. Packages of care for dementia in low- and middle-income countries. PLoS Med 2009; 6 (11) e1000176
    CrossrefPubMedGoogle Scholar
  • 6 Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007; 3 (03) 186-191
    CrossrefPubMedGoogle Scholar
  • 7 Ahmad SS, Akhtar S, Jamal QM. , et al. Multiple targets for the management of Alzheimer's disease. CNS Neurol Disord Drug Targets 2016; 15 (10) 1279-1289
    CrossrefPubMedGoogle Scholar
  • 8 Meyer PF, Savard M, Poirier J, Morgan D, Breitner J. ; Alzheimer's Disease Neuroimaging Initiative. Hypothesis: cerebrospinal fluid protein markers suggest a pathway toward symptomatic resilience to AD pathology. Alzheimers Dement 2019; ;•••: 1-12
    PubMedGoogle Scholar
  • 9 Chen GF, Xu TH, Yan Y. , et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 2017; 38 (09) 1205-1235
    CrossrefPubMedGoogle Scholar
  • 10 Haass C, Selkoe DJ. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 1993; 75 (06) 1039-1042
    CrossrefPubMedGoogle Scholar
  • 11 Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. 1984. Biochem Biophys Res Commun 2012; 425 (03) 534-539
    CrossrefPubMedGoogle Scholar
  • 12 Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 2016; 8 (06) 595-608
    CrossrefPubMedGoogle Scholar
  • 13 Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann Neurol 2011; 70 (06) 871-880
    CrossrefPubMedGoogle Scholar
  • 14 Nunan J, Small DH. Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett 2000; 483 (01) 6-10
    CrossrefPubMedGoogle Scholar
  • 15 Reitz C. Alzheimer's disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis 2012; 2012: 369808
    PubMedGoogle Scholar
  • 16 About a peculiar disease of the cerebral cortex. By Alois Alzheimer, 1907 (Translated by L. Jarvik and H. Greenson). Alzheimer Dis Assoc Disord 1987; 1 (01) 3-8
    PubMedGoogle Scholar
  • 17 Michaelis ML. Drugs targeting Alzheimer's disease: some things old and some things new. J Pharmacol Exp Ther 2003; 304 (03) 897-904
    CrossrefPubMedGoogle Scholar
  • 18 Murphy MP, LeVine III H. Alzheimer's disease and the amyloid-β peptide. J Alzheimers Dis 2010; 19 (01) 311-323
    CrossrefPubMedGoogle Scholar
  • 19 Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs 2006; 66 (11) 1515-1534
    CrossrefPubMedGoogle Scholar
  • 20 Ghezzi L, Scarpini E, Galimberti D. Disease-modifying drugs in Alzheimer's disease. Drug Des Devel Ther 2013; 7: 1471-1478
    PubMedGoogle Scholar
  • 21 Stites SD, Rubright JD, Karlawish J. What features of stigma do the public most commonly attribute to Alzheimer's disease dementia? Results of a survey of the U.S. general public. Alzheimers Dement 2018; 14 (07) 925-932
    CrossrefPubMedGoogle Scholar
  • 22 Lundkvist J, Halldin MM, Sandin J. , et al. The battle of Alzheimer's disease - the beginning of the future unleashing the potential of academic discoveries. Front Pharmacol 2014; 5: 102
    PubMedGoogle Scholar
  • 23 Schneider LS, Mangialasche F, Andreasen N. , et al. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med 2014; 275 (03) 251-283
    CrossrefPubMedGoogle Scholar
  • 24 Zheng H, Fridkin M, Youdim M. New approaches to treating Alzheimer's disease. Perspect Medicin Chem 2015; 7: 1-8
    PubMedGoogle Scholar
  • 25 Wisniewski T, Goñi F. Immunotherapy for Alzheimer's disease. Biochem Pharmacol 2014; 88 (04) 499-507
    CrossrefPubMedGoogle Scholar
  • 26 Jia Q, Deng Y, Qing H. Potential therapeutic strategies for Alzheimer's disease targeting or beyond β-amyloid: insights from clinical trials. BioMed Res Int 2014; 2014: 837157
    PubMedGoogle Scholar
  • 27 Kumar A, Singh A. , Ekavali. A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep 2015; 67 (02) 195-203
    CrossrefPubMedGoogle Scholar
  • 28 Re F, Airoldi C, Zona C. , et al. Beta amyloid aggregation inhibitors: small molecules as candidate drugs for therapy of Alzheimer's disease. Curr Med Chem 2010; 17 (27) 2990-3006
    CrossrefPubMedGoogle Scholar
  • 29 Judge D, Roberts J, Khandker R, Ambegaonkar B, Black CM. Physician perceptions about the barriers to prompt diagnosis of mild cognitive impairment and Alzheimer's disease. Int J Alzheimers Dis 2019; 2019: 3637954
    PubMedGoogle Scholar
  • 30 Bush AI. Metal complexing agents as therapies for Alzheimer's disease. Neurobiol Aging 2002; 23 (06) 1031-1038
    CrossrefPubMedGoogle Scholar
  • 31 Taniguchi S, Suzuki N, Masuda M. , et al. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem 2005; 280 (09) 7614-7623
    CrossrefPubMedGoogle Scholar
  • 32 Pollack SJ, Sadler IIJ, Hawtin SR, Tailor VJ, Shearman MS. Sulfonated dyes attenuate the toxic effects of β-amyloid in a structure-specific fashion. Neurosci Lett 1995; 197 (03) 211-214
    CrossrefPubMedGoogle Scholar
  • 33 Porat Y, Abramowitz A, Gazit E. Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 2006; 67 (01) 27-37
    CrossrefPubMedGoogle Scholar
  • 34 Reinke AA, Gestwicki JE. Structure-activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chem Biol Drug Des 2007; 70 (03) 206-215
    CrossrefPubMedGoogle Scholar
  • 35 Wu C, Scott J, Shea JE. Binding of Congo red to amyloid protofibrils of the Alzheimer Aβ(9-40) peptide probed by molecular dynamics simulations. Biophys J 2012; 103 (03) 550-557
    CrossrefPubMedGoogle Scholar
  • 36 Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A 1994; 91 (25) 12243-12247
    CrossrefPubMedGoogle Scholar
  • 37 Xie Y, Deng S, Chen Z, Yan S, Landry DW. Identification of small-molecule inhibitors of the Abeta-ABAD interaction. Bioorg Med Chem Lett 2006; 16 (17) 4657-4660
    CrossrefPubMedGoogle Scholar
  • 38 Bu XL, Rao PPN, Wang YJ. Anti-amyloid aggregation activity of natural compounds: implications for Alzheimer's drug discovery. Mol Neurobiol 2016; 53 (06) 3565-3575
    CrossrefPubMedGoogle Scholar
  • 39 Velander P, Wu L, Henderson F, Zhang S, Bevan DR, Xu B. Natural product-based amyloid inhibitors. Biochem Pharmacol 2017; 139: 40-55
    CrossrefPubMedGoogle Scholar
  • 40 Savelieff MG, DeToma AS, Derrick JS, Lim MH. The ongoing search for small molecules to study metal-associated amyloid-β species in Alzheimer's disease. Acc Chem Res 2014; 47 (08) 2475-2482
    CrossrefPubMedGoogle Scholar
  • 41 Korshavn KJ, Jang M, Kwak YJ. , et al. Reactivity of metal-free and metal-associated amyloid-beta with glycosylated polyphenols and their esterified derivatives. Sci Rep 2015; 5: 17842
    CrossrefPubMedGoogle Scholar
  • 42 Nie Q, Du XG, Geng MY. Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease. Acta Pharmacol Sin 2011; 32 (05) 545-551
    CrossrefPubMedGoogle Scholar
  • 43 NIH. U.S National Library of Medicine. Clinical Trials.gov publication. Safety and efficacy study ofALZT-OP1 in subjects with evidence of early Alzheimer's disease (NCT02547818). Available at: https://clinicaltrials.gov/ct2/show/NCT02547818 . Accessed September 11, 2015
    Google Scholar
  • 44 NIH. U.S National Library of Medicine. Clinical Trials.gov publication. Safety, efficacy and dose titration of Sodium Oligo-mannurarate capsule on mild to moderate Alzheimer's disease (NCT01453569). Available at: https://clinicaltrials.gov/ct2/show/NCT01453569 . Accessed October 18, 2011.
    Google Scholar
  • 45 NIH. U.S National Library of Medicine. Clinical Trials.gov publication. An efficacy and safety study of sodium Oligo-mannurarate (GV-971) capsule for the treatment of Alzheimer's disease (NCT02293915). Available at: https://clinicaltrials.gov/ct2/show/NCT02293915 . Accessed November 19, 2014
    Google Scholar
  • 46 NIH. U.S National Library of Medicine. Clinical Trials.gov publication. A study of single and multiple doses of KHK6640 in subjects with prodromal or mild to moderate Alzheimer's disease (NCT02127476). Available at: https://clinicaltrials.gov/ct2/show/NCT02127476 . Accessed April 30, 2014
    Google Scholar
  • 47 Bachurin SO, Bovina EV, Ustyugov AA. Drugs in clinical trials for Alzheimer's disease: the major trends. Med Res Rev 2017; 37 (05) 1186-1225
    CrossrefPubMedGoogle Scholar
  • 48 Sinha S, Du Z, Maiti P. , et al. Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. ACS Chem Neurosci 2012; 3 (06) 451-458
    CrossrefPubMedGoogle Scholar
  • 49 Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry 2012; 83 (09) 894-902
    CrossrefPubMedGoogle Scholar
  • 50 Bachurin SO, Bovina EV, Ustyugov AA. Current trends in the development of drugs for the treatment of Alzheimer's disease and their clinical trials. Biomed Chem Res Methods 2018; 1 (03) e00015
    Google Scholar
  • 51 Suhr OB, Lundgren E, Westermark P. Transthyretin amyloidoses: new strategies for therapeutic intervention. Drugs Future 2010; 35: 325
    CrossrefGoogle Scholar
  • 52 Vartiainen NE, Williams M, Charles ML, Stenius T, Nurmi A, Yrjanheikki J. SAN-61 protects against Aβ1–42, OGD and H2O2 in rat mixed cortical cultures and inhibits GSK- 3b. Paper presented at: 39th Society for Neuroscience Meeting; October 16, 2009; Chicago, United States
    Google Scholar
  • 53 Hu Q, Cam J, Lake T. , et al. Identification of Exebryl-1 and other novel small molecules as tau protein aggregation inhibitors. Alzheimer's & Dementia: J Alzheimer's Assoc 2011; 4: 481
    Google Scholar
  • 54 Zou K, Gong JS, Yanagisawa K, Michikawa M. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 2002; 22 (12) 4833-4841
    CrossrefPubMedGoogle Scholar
  • 55 Danielsson J, Jarvet J, Damberg P, Gräslund A. The Alzheimer beta-peptide shows temperature-dependent transitions between left-handed 3-helix, beta-strand and random coil secondary structures. FEBS J 2005; 272 (15) 3938-3949
    CrossrefPubMedGoogle Scholar
  • 56 Yang DS, Yip CM, Huang TH, Chakrabartty A, Fraser PE. Manipulating the amyloid-beta aggregation pathway with chemical chaperones. J Biol Chem 1999; 274 (46) 32970-32974
    CrossrefPubMedGoogle Scholar
  • 57 Liu YH, Giunta B, Zhou HD, Tan J, Wang YJ. Immunotherapy for Alzheimer disease: the challenge of adverse effects. Nat Rev Neurol 2012; 8 (08) 465-469
    CrossrefPubMedGoogle Scholar
  • 58 Xu Y, Shen J, Luo X. , et al. Conformational transition of amyloid beta-peptide. Proc Natl Acad Sci U S A 2005; 102 (15) 5403-5407
    CrossrefPubMedGoogle Scholar
  • 59 Landau M, Sawaya MR, Faull KF. , et al. Towards a pharmacophore for amyloid. PLoS Biol 2011; 9 (06) e1001080
    CrossrefPubMedGoogle Scholar
  • 60 Rajasekhar K, Suresh SN, Manjithaya R, Govindaraju T. Rationally designed peptidomimetic modulators of aβ toxicity in Alzheimer's disease. Sci Rep 2015; 5: 8139
    CrossrefPubMedGoogle Scholar
  • 61 Arai T, Sasaki D, Araya T, Sato T, Sohma Y, Kanai M. A cyclic KLVFF-derived peptide aggregation inhibitor induces the formation of less-toxic off-pathway amyloid-β oligomers. ChemBioChem 2014; 15 (17) 2577-2583
    CrossrefPubMedGoogle Scholar
  • 62 Gazit E. Mechanistic studies of the process of amyloid fibrils formation by the use of peptide fragments and analogues: implications for the design of fibrillization inhibitors. Curr Med Chem 2002; 9 (19) 1725-1735
    CrossrefPubMedGoogle Scholar
  • 63 Gazit E. Global analysis of tandem aromatic octapeptide repeats: the significance of the aromatic-glycine motif. Bioinformatics 2002; 18 (06) 880-883
    CrossrefPubMedGoogle Scholar
  • 64 Sarasa M, Pesini P. Natural non-trasgenic animal models for research in Alzheimer's disease. Curr Alzheimer Res 2009; 6 (02) 171-178
    CrossrefPubMedGoogle Scholar
  • 65 Dai X, Chang P, Liu W. , et al. Aβ-40 Y10F increases βfibrils formation but attenuates the neurotoxicity of amyloid-β peptide. Int J Mol Sci 2012; 13 (05) 5324-5337
    CrossrefPubMedGoogle Scholar
  • 66 Barnham KJ, Haeffner F, Ciccotosto GD. , et al. Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease beta-amyloid. FASEB J 2004; 18 (12) 1427-1429
    CrossrefPubMedGoogle Scholar
  • 67 Schöneich C. Methionine oxidation by reactive oxygen species: reaction mechanisms and relevance to Alzheimer's disease. Biochim Biophys Acta 2005; 1703 (02) 111-119
    CrossrefPubMedGoogle Scholar
  • 68 Yang DS, McLaurin J, Qin K, Westaway D, Fraser PE. Examining the zinc binding site of the amyloid-beta peptide. Eur J Biochem 2000; 267 (22) 6692-6698
    CrossrefPubMedGoogle Scholar
  • 69 Cheng B, Gong H, Xiao H, Petersen RB, Zheng L, Huang K. Inhibiting toxic aggregation of amyloidogenic proteins: a therapeutic strategy for protein misfolding diseases. Biochim Biophys Acta 2013; 1830 (10) 4860-4871
    CrossrefPubMedGoogle Scholar
  • 70 Yanagisawa D, Taguchi H, Yamamoto A, Shirai N, Hirao K, Tooyama I. Curcuminoid binds to amyloid-β1-42 oligomer and fibril. J Alzheimers Dis 2011; 24 (Suppl. 02) 33-42
    CrossrefPubMedGoogle Scholar
  • 71 Masuda Y, Fukuchi M, Yatagawa T. , et al. Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils. Bioorg Med Chem 2011; 19 (20) 5967-5974
    CrossrefPubMedGoogle Scholar
  • 72 Orlando RA, Gonzales AM, Royer RE, Deck LM, Vander Jagt DL. A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization. PLoS One 2012; 7 (03) e31869
    CrossrefPubMedGoogle Scholar
  • 73 Sato T, Kienlen-Campard P, Ahmed M. , et al. Inhibitors of amyloid toxicity based on beta-sheet packing of Abeta40 and Abeta42. Biochemistry 2006; 45 (17) 5503-5516
    CrossrefPubMedGoogle Scholar
  • 74 Zhao LN, Chiu SW, Benoit J, Chew LY, Mu Y. The effect of curcumin on the stability of Aβ dimers. J Phys Chem B 2012; 116 (25) 7428-7435
    CrossrefPubMedGoogle Scholar
  • 75 Rao PP, Mohamed T, Teckwani K, Tin G. Curcumin binding to beta amyloid: a computational study. Chem Biol Drug Des 2015; 86 (04) 813-820
    CrossrefPubMedGoogle Scholar
  • 76 Ge JF, Qiao JP, Qi CC, Wang CW, Zhou JN. The binding of resveratrol to monomer and fibril amyloid beta. Neurochem Int 2012; 61 (07) 1192-1201
    CrossrefPubMedGoogle Scholar
  • 77 Feng Y, Wang XP, Yang SG. , et al. Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. Neurotoxicology 2009; 30 (06) 986-995
    CrossrefPubMedGoogle Scholar
  • 78 Ladiwala AR, Lin JC, Bale SS. , et al. Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers. J Biol Chem 2010; 285 (31) 24228-24237
    CrossrefPubMedGoogle Scholar
  • 79 Ladiwala AR, Mora-Pale M, Lin JC. , et al. Polyphenolic glycosides and aglycones utilize opposing pathways to selectively remodel and inactivate toxic oligomers of amyloid β. ChemBioChem 2011; 12 (11) 1749-1758
    CrossrefPubMedGoogle Scholar
  • 80 Rezai-Zadeh K, Shytle D, Sun N. , et al. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 2005; 25 (38) 8807-8814
    CrossrefPubMedGoogle Scholar
  • 81 Bieschke J, Russ J, Friedrich RP. , et al. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A 2010; 107 (17) 7710-7715
    CrossrefPubMedGoogle Scholar
  • 82 Rauk A. Why is the amyloid beta peptide of Alzheimer's disease neurotoxic?. Dalton Trans 2008; (10) 1273-1282
    PubMedGoogle Scholar
  • 83 Shaw JE, Chio J, Dasgupta S. , et al. Aβ(1-42) assembly in the presence of scyllo-inositol derivatives: identification of an oxime linkage as important for the development of assembly inhibitors. ACS Chem Neurosci 2012; 3 (03) 167-177
    CrossrefPubMedGoogle Scholar
  • 84 Sun Y, Zhang G, Hawkes CA, Shaw JE, McLaurin J, Nitz M. Synthesis of scyllo-inositol derivatives and their effects on amyloid beta peptide aggregation. Bioorg Med Chem 2008; 16 (15) 7177-7184
    CrossrefPubMedGoogle Scholar
  • 85 O'Hare E, Scopes DI, Treherne JM, Norwood K, Spanswick D, Kim EM. RS-0406 arrests amyloid-β oligomer-induced behavioural deterioration in vivo. Behav Brain Res 2010; 210 (01) 32-37
    CrossrefPubMedGoogle Scholar
  • 86 Nakagami Y, Nishimura S, Murasugi T. , et al. A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro. Br J Pharmacol 2002; 137 (05) 676-682
    CrossrefPubMedGoogle Scholar
  • 87 Mohamed T, Shakeri A, Rao PP. Amyloid cascade in Alzheimer's disease: recent advances in medicinal chemistry. Eur J Med Chem 2016; 113: 258-272
    CrossrefPubMedGoogle Scholar
  • 88 López LC, Dos-Reis S, Espargaró A. , et al. Discovery of novel inhibitors of amyloid β-peptide 1-42 aggregation. J Med Chem 2012; 55 (22) 9521-9530
    CrossrefPubMedGoogle Scholar
  • 89 Luo W, Li YP, He Y. , et al. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as dual inhibitors for cholinesterases and amyloid beta aggregation. Bioorg Med Chem 2011; 19 (02) 763-770
    CrossrefPubMedGoogle Scholar
  • 90 Arai T, Araya T, Sasaki D. , et al. Rational design and identification of a non-peptidic aggregation inhibitor of amyloidb based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-]. Angew Chem Int Ed Engl 2014; 53 (31) 8236-8239
    CrossrefPubMedGoogle Scholar
  • 91 Guzior N, Bajda M, Skrok M. , et al. Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective properties. Eur J Med Chem 2015; 92: 738-749
    CrossrefPubMedGoogle Scholar
  • 92 Kroth H, Ansaloni A, Varisco Y. , et al. Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation. J Biol Chem 2012; 287 (41) 34786-34800
    CrossrefPubMedGoogle Scholar
  • 93 Veloso AJ, Dhar D, Chow AM. , et al. sym-Triazines for directed multitarget modulation of cholinesterases and amyloid-β in Alzheimer's disease. ACS Chem Neurosci 2013; 4 (02) 339-349
    CrossrefPubMedGoogle Scholar
  • 94 Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer's disease drug development pipeline: 2019. Alzheimers Dement (N Y) 2019; 5: 272-293
    Google Scholar
  • 95 Cummings J, Lee G, Ritter A, Zhong K. Alzheimer's disease drug development pipeline: 2018. Alzheimers Dement (N Y) 2018; 4: 195-214
    Google Scholar