Current and novel therapeutic molecules and targets in Alzheimer's disease

Journal of the Formosan Medical Association

Volumn 115, Issue 1, 2016, Pages 3-10

  Kumar, Ashwini ^a   Nisha, Chaluveelaveedu Murleedharan ^a   Silakari, Chitrangda ^a   Sharma, Isha ^a   Anusha, Kanukanti ^a   Gupta, Nityasha ^a   Nair, Prateek ^a   Tripathi, Timir ^b   Kumar, Awanish ^a  

^a NATIONAL INSTITUTE OF TECHNOLOGY   (India)

^b NORTH EASTERN HILL UNIVERSITY   (India)

Author keywords

Alzheimer's disease; Drug targets; Inhibitors; Molecular docking; Therapy

Indexed keywords

ACETYLCHOLINESTERASE; BETA SECRETASE; MUSCARINIC RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NICOTINIC RECEPTOR; TAU PROTEIN;

ALZHEIMER DISEASE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MOLECULAR DOCKING; NONHUMAN; REVIEW; BRAIN; DRUG DESIGN; PATHOPHYSIOLOGY;

ALZHEIMER DISEASE; BRAIN; DRUG DESIGN; HUMANS; MOLECULAR DOCKING SIMULATION;

EID: 84958772667     PISSN: 09296646     EISSN: 18760821     Source Type: Journal    
DOI: 10.1016/j.jfma.2015.04.001     Document Type: Review

References (83)

1. Alzheimer's Association Alzheimer's disease facts and figures. Alzheimers Dement 2013, 9:1-61.
2. Selkoe D.J. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 2001, 81:2.
3. Noble W., Hanger D.P., Miller C.C.J., Lovestone S. The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 2013, 4:83.
4. Zhang Y.W., Thompson R., Zhang H., Xu H. APP processing in Alzheimer's disease. Mol Brain 2011, 4:3.
5. De-Paula V.J., Radanovic M., Diniz B.S., Forlenza O.V. Alzheimer's disease. Subcell Biochem 2012, 65:329-352.
6. Bäckman L., Jones S., Berger A.K., Laukka E.J., Small B.J. Multiple cognitive deficits during the transition to Alzheimer's disease. J Intern Med 2004, 256:195-204.
7. Croisile B., Auriacombe S., Etcharry-Bouyx F., Vercelletto M. The new 2011 recommendations of the National Institute on Aging and the Alzheimer's Association on diagnostic guidelines for Alzheimer's disease: Preclinical stages, mild cognitive impairment, and dementia. Rev Neurol (Paris) 2012, 168:471-482.
8. Hebert L.E., Weuve J., Scherr P.A., Evans D.A. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013, 80:1778-1783.
9. Brookmeyer R., Johnson E., Ziegler-Graham K., Arrighi H.M. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007, 3:186-191.
10. Niedowicz D.M., Nelson P.T., Murphy M.P. Alzheimer's disease: Pathological mechanisms and recent insights. Curr Neuropharmacol 2011, 9:674-684.
11. Lacor P.N., Buniel M.C., Furlow P.W., Clemente A.S., Velasco P.T., Wood M., et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci 2007, 27:796-807.
12. Yankner B.A., Duffy L.K., Kirschner D.A. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 1990, 250:279-282.
13. Shen Z.X. Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease. Med Hypotheses 2004, 63:308-321.
14. Wenk G.L. Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry 2003, 64:S7-10.
15. Chun W., Johnson G.V. The role of tau phosphorylation and cleavage in neuronal cell death. Front Biosci 2007, 12:733-756.
16. Blennow K., de Leon M.J., Zetterberg H. Alzheimer's disease. Lancet 2006, 368:387-403.
17. Waring S.C., Rosenberg R.N. Genome-wide association studies in Alzheimer disease. Arch Neurol 2008, 65:329-334.
18. Shioi J., Georgakopoulos A., Mehta P., Kouchi Z., Litterst C.M., Baki L., et al. FAD mutants unable to increase neurotoxic Aβ 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem 2007, 101:674-681.
19. Fassbender K., Masters C., Beyreuther K. Alzheimer's disease: molecular concepts and therapeutic targets. Naturwissenschaften 2001, 88:261-267.
20. Strittmatter W.J. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci 1993, 90:1977-1981.
21. Mahley R.W., Weisgraber K.H., Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc Natl Acad Sci 2006, 103:5644-5651.
22. Ou-Yang S.S., Lu J.Y., Kong X.Q., Liang Z.J., Luo C., Jiang H. Computational drug discovery. Acta Pharmacol Sin 2012, 33:1131-1140.
23. Ooms F. Molecular modeling and computer aided drug design. Examples of their applications in medicinal chemistry. Curr Med Chem 2000, 7:141-158.
24. Alzheimer's Association. Younger/early onset Alzheimer's and dementia. [accessed 10.07.15]. https://www.alz.org/national/documents/brochure_earlyonset.pdf.
25. Lane R.M., Potkin S.G., Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol 2006, 9:101-124.
26. Thompson P.A., Wright D.E., Counsell C.E., Zajisek J. Statistical analysis, trial design and duration in Alzheimer's disease clinical trials: a review. Int Psychogeriatr 2012, 24:689-697.
27. Turner P.R., O'Connor K., Tate W.P., Abraham W.C. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 2003, 70:1-32.
28. Colović M.B., Krstić D.Z., Lazarević-Pašti T.D., Bondzic A.M., Vasic V.M. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 2013, 11:315-335.
29. Giacobini E. Cholinesterase inhibitors: new roles and therapeutic alternatives. Pharmacol Res 2004, 50:433-440.
30. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006, 1:CD005593.
31. Teipel S., Heinsen H., Amaro E., Grinberg L.T., Krause B., Grothe M., et al. Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease. Neurobiol Aging 2014, 35:482-491.
32. Armstrong R.A. What causes Alzheimer's disease?. Folia Neuropathol 2013, 51:169-188.
33. Jacobsen J.S., Reinhart P., Pangalos M.N. Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease. Neuro Rx 2005, 2:612-626.
34. Sheng R., Lin X., Zhang J., Chol K.S., Huang W., Yang B., et al. Design, synthesis and evaluation of flavonoid derivatives as potent AChE inhibitors. Bioorg Med Chem 2009, 17:6692-6698.
35. Khan M.T., Orhan I., Senol F.S., Kartal M., Sener B., Dvorska M., et al. Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chem Biol Interact 2009, 181:383-389.
36. Roy K.K., Tota S., Tripathi T., Chander S., Nath C., Saxena A.K. Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer's disease. Bioorg Med Chem 2012, 20:6313-6320.
37. Basiri A., Murugaiyah V., Osman H., Kumar R.S., Kia Y., Ali M.A. Microwave assisted synthesis, cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives. Bioorg Med Chem 2013, 21:3022-3031.
38. Samadi A., Estrada M., Pérez C., Franco M.I.R., Iriepa I., Moraleda I., et al. Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: synthesis, biological assessment, and molecular modeling. Eur J Med Chem 2012, 57:296-301.
39. Samadi A., Revenga M.F., Pérez C., Iriepa I., Moraleda I., Franco M.I.R., et al. Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease. Eur J Med Chem 2013, 67:64-74.
40. Varadaraju K.R., Kumar J.R., Mallesha L., Muruli A., Mohana K.N.S., Mukunda C.K., et al. Virtual screening and biological evaluation of piperazine derivatives as human acetylcholinesterase inhibitors. Int J Alzheimers Dis 2013, 2013:653962.
41. Lipton S.A. The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res 2005, 2:155-165.
42. Dingledine R., Borges K., Bowie D., Traynelis S.F. The glutamate receptor ion channels. Pharmacol Rev 1999, 51:7-61.
43. Zhou Y., Danbolt N.C. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm 2014, 121:799-817.
44. Danysz W., Parsons C.G. Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine-searching for the connections. Br J Pharmacol 2012, 167:324-352.
45. Paoletti P., Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol 2007, 7:39-47.
46. Parson C.G., Danysz W., Dekundy A., Pulte I. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. Neurotox Res 2013, 24:358-369.
47. Colotta V., Lenzi O., Catarzi D., Varano F., Squarcialupi L., Costagli C., et al. 3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies. Eur J Med Chem 2012, 54:470-482.
48. Espinoza-Moraga M., Caballero J., Gaube F., Winckler T., Santos L.S. 1-Benzyl-1,2,3,4-tetrahydro-β-carboline as channel blocker of N-methyl-D-aspartate receptors. Chem Biol Drug Des 2012, 79:594-599.
49. Gitto R., De Luca L., Ferro S., Ruso E., Sarro G.D., Chisari M., et al. Synthesis, modeling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors. Bioorg Med Chem 2014, 22:1040-1048.
50. Abreu P.A., Castro H.C., Paes-de-Carvalho R., Rodrigues C.R., Giongo V., Paixao I.C., et al. Molecular modeling of a phenyl-amidine class of NMDA receptor antagonists and the rational design of new triazolyl-amidine derivatives. Chem Biol Drug Des 2013, 81:185-197.
51. Krueger B.A., Weil T., Schneider G. Comparative virtual screening and novelty detection for NMDA-GlycineB antagonists. J Comput Aided Mol Des 2009, 23:869-881.
52. Gitto R., De Luca L., Ferro S., Occhiuto F., Samperi S., De Sarro G., et al. Computational studies to discover a new NR2B/NMDA receptor antagonist and evaluation of pharmacological profile. Chem Med Chem 2008, 3:1539-1548.
53. Caulfield M.P., Bridsall N.J. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998, 50:279-290.
54. Jiang S., Li Y., Zhang C., Zhao Y., Bu G., Xu H., et al. M1 muscarinic acetylcholine receptor in Alzheimer's disease. Neurosci Bull 2014, 30:295-307.
55. Buckingham S.D., Jones A.K., Brown L.A., Sattelle D.B. Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. Pharmaol Rev 2009, 61:39-61.
56. Davie B.J., Christopoulos A., Scammells P.J. Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits. ACS Chem Neurosci 2013, 4:1026-1048.
57. Foster D.J., Choi D.L., Conn P.J., Rook J.M. Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia. Neuropsychiatr Dis Treat 2014, 10:183-191.
58. Melancon B.J., Tarr J.C., Panarese J.D., Wood M.R., Lindsley C.W. Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease. Drug Discov Today 2013, 18:1185-1199.
59. A randomized, double-blind, placebo-controlled, parallel, 24-week, Phase 2 study of three different doses of an alpha-7 nicotinic acetylcholine receptor agonist (EVP-6124) or placebo in subjects with mild to moderate probable Alzheimer's disease. Identifier No. [accessed 10.07.15]. https://clinicaltrials.gov/ct2/show/NCT01073228?term=NCT01073228&rank=1.
60. Balaraman Y., Limaye A.R., Levey A.I., Srinivasan S. Glycogen synthase kinase 3β and Alzheimer's disease: pathophysiological and therapeutic significance. Cell Mol Life Sci 2006, 63:1226-1235.
61. Hernandez F., Avila J. Tauopathies. Cell Mol Life Sci 2007, 64:2219-2233.
62. Uehara F., Shoda A., Aritomo K., Fukunaga K., Watanabe K., Ando R., et al. 6-(4-Pyridyl)pyrimidin-4(3H)-ones as CNS penetrant glycogen synthase kinase-3β inhibitors. Bioorg Med Chem Lett 2013, 23:6928-6932.
63. Hanger D.P., Anderton B.H., Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 2009, 15:112-119.
64. Saido T.C. Metabolism of amyloid β peptide and pathogenesis of Alzheimer's disease. Proc Jpn Acad Ser 2013, 89:321-339.
65. Vassar R., Kandalepas P.C. The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease. Alz Res Ther 2013, 3:1-6.
66. Mancini F., De Simone A., Andrisano V. Beta-secretase as a target for Alzheimer's disease drug discovery: an overview of in vitro methods for characterization of inhibitors. Anal Bioanal Chem 2011, 400:1979-1996.
67. Ghosh A.K., Gemma S., Tang J. β-Secretase as a therapeutic target for Alzheimer's disease. Neurotherapeutics 2008, 5:399-408.
68. Ghosh A.K., Brindisi M., Tang J. Developing β-secretase inhibitors for treatment of Alzheimer's disease. J Neurochem 2012, 120:71-83.
69. Piazzi L., Cavalli A., Colizzi F., Belluti F., Bartolini M., Mancini F., et al. Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorg Med Chem Lett 2008, 18:423-426.
70. Zhu Y., Xiao K., Ma L., Xiong B., Fu Y., Yu H., et al. Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase. Bioorg Med Chem 2009, 17:1600-1613.
71. Shimmyo Y., Kihara T., Akaike A., Niidome T., Sugimoto H. Flavonols and flavones as BACE-1 inhibitors: Structure - activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features. Biochim Biophys Acta 2008, 1780:819-825.
72. Zuo Z., Luo X., Zhu W., Shen J., Shen X., Jiang H., et al. Molecular docking and 3D-QSAR studies on the binding mechanism of statine-based peptidomimetics with β-secretase. Bioorg Med Chem 2005, 13:2121-2131.
73. Remya C., Dileep K.V., Tintu I., Variyar E.J., Sadasivan C. In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile. J Mol Model 2013, 19:1179-1194.
74. Razavi S.F., Khoobi M., Nadri H., Sakhteman A., Moradi A., Emami S., et al. Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors. Eur J Med Chem 2013, 64:252-259.
75. Kwon Y.E., Park J.Y., No K.T., Shin J.H., Lee S.K., Eun J.S., et al. Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Aβ 1-42 aggregation for Alzheimer's disease therapeutics. Bioorg Med Chem 2007, 15:6596-6607.
76. Butini S., Gabellieri E., Brindisi M., Casagni A., Guarino E., Huleatt P.B., et al. Novel peptidomimetics as BACE-1 inhibitors: Synthesis, molecular modeling, and biological studies. Bioorg Med Chem Lett 2013, 23:85-89.
77. Truong A.P., Toth G., Probst G.D., Sealy J.M., Bowers S., Wone D.W.G., et al. Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model. Bioorg Med Chem Lett 2010, 20:6231-6236.
78. Fukumoto H., Takahashi H., Tarui N., Matsui J., Tomita T., Hirode M., et al. A noncompetitive BACE1 inhibitor TAK-070 ameliorates Aβ pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci 2010, 30:11157-11166.
79. A single-center, randomized, double-blinded, placebo-controlled, 4-way cross-over study to assess the effect of a single oral dose of AZD3293 administration on QTc interval compared to placebo, using open-label AVELOX (Moxifloxacin) as a positive control, in healthy male subjects. AZD3293 Trial. Identifier No. [accessed 10.07.15]. https://clinicaltrials.gov/ct2/show/NCT02040987?term=NCT02040987&rank=1.
80. A randomized, placebo controlled, parallel-group, double blind efficacy and safety trial of MK-8931 with a long term double-blind extension in subjects with mild to moderate Alzheimer's disease (Protocol No. MK-8931-017-10) (also known as SCH 900931, P07738). MK-8931 Trial. Identifier No. [accessed 10.07.15]. https://clinicaltrials.gov/ct2/show/NCT01739348?term=NCT01739348&rank=1.
81. Potter P.E. Investigational medications for treatment of patients with Alzheimer disease. J Am Osteopath Assoc 2010, 110:S27-36.
82. Randomized, double-blind, placebo-controlled, parallel-group, 18-month safety and efficacy study of TRx0237 in subjects with mild Alzheimer's disease. TRx0237 trial. Identifier No. [accessed 10.07.15]. https://clinicaltrials.gov/ct2/show/NCT01689233?term=NCT01689233&rank=1.
83. TauRx Therapeutics Achieves Enrollment Target for Second Phase III Clinical Trial of LMTX™ in Alzheimer's Disease. TauRx Therapeutics. [accessed 10.07.15]. http://taurx.com/taurx-005-enrolment.html.