Alzheimer's disease: Emerging trends in small molecule therapies

Current Medicinal Chemistry

Volumn 18, Issue 28, 2011, Pages 4299-4320

  Mohamed, T ^a   Rao, P P N ^a  

^a UNIVERSITY OF WATERLOO   (Canada)

Author keywords

secretase; Alzheimer's disease; Amyloid plaques; Amyloid precursor protein; Cholinesterase; Disease modifying agents; Neurofibrillary tangles; Reactive oxygen species; Tau protein.

Indexed keywords

10 HYDROXYINFRACTOPICRIN; ACETYLCHOLINESTERASE; AMYLOID BETA PROTEIN; BETA SECRETASE INHIBITOR; BIS 7 TACRINE; CHELATING AGENT; CHOLINESTERASE; CLIOQUINOL; DONEPEZIL; EDROPHONIUM; ETANERCEPT; GALANTAMINE; GAMMA SECRETASE INHIBITOR; HUPERZINE A; INFRACTOPICRIN; MELATONIN; MEMANTINE; MONOAMINE OXIDASE INHIBITOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NONSTEROID ANTIINFLAMMATORY AGENT; OM 99 2; PHENSERINE; RASAGILINE; REACTIVE OXYGEN METABOLITE; RIVASTIGMINE; SCAVENGER; TACRINE; TAU PROTEIN; TETRAHYDROFUROBENZOFURAN CYMSERINE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALZHEIMER DISEASE; AMYLOID PLAQUE; COGNITIVE DEFECT; DEGENERATIVE DISEASE; DRUG HALF LIFE; DRUG ISOLATION; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; HUMAN; IC 50; NEUROFIBRILLARY TANGLE; NEUROPROTECTION; NONHUMAN; PATHOGENESIS; REVIEW; STRUCTURE ACTIVITY RELATION;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; CHOLINERGIC AGONISTS; CHOLINESTERASE INHIBITORS; DRUG THERAPY; HUMANS; REACTIVE OXYGEN SPECIES; RECEPTORS, N-METHYL-D-ASPARTATE; SMALL MOLECULE LIBRARIES; TAU PROTEINS;

EID: 80052921123     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986711797200435     Document Type: Review

References (175)

1. Suh, W. H.; Suslick, K. S.; Suh, Y. H. Therapeutic agents for Alzheimer's disease. Curr. Med. Chem., 2005, 5, 259-269. (Pubitemid 41702297)
2. Klafki, H. W.; Staufenbiel, M.; Kornhuber, J.; Wiltfang, J. Therapeutic approaches to Alzheimer's disease. Brain, 2006, 129, 2840-2855. (Pubitemid 44684507)
3. Hirono, N.; Hashimoto, M.; Yasuda, M.; Kazui, H.; Mori, E. Accelerated memory decline in Alzheimer's disease with apolipoprotein ε4 allele. J. Neuropsychiatry Clin. Neurosci., 2003, 15, 354-358. (Pubitemid 36999379)
4. Edwards, P. D.; Albert, J. S.; Sylvester, M.; Aharony, D.; Andisik, D.; Callaghan, O.; Campbell, J. B.; Carr, R. A.; Chessari, G.; Congreve, M.; Frederickson, M.; Folmer, R. H. A.; Geschwindner, S.; Koether, G.; Kolmodin, K.; Krumrine, J.; Mauger, R. C.; Murray, C. W.; Olsson, L.; Patel, S.; Spear, N.; Tian, G. Application of fragment-based lead generation to the discovery of novel, cyclic amidine & beta; -secretase inhibitors with nano molar potency, cellular activity, and high ligand efficiency. J. Med. Chem., 2007, 50, 5912-5925.
5. Selkoe, D. J. Alzheimer's disease is a synaptic failure. Science, 2002, 298, 789-791. (Pubitemid 35231524)
6. Minati, L.; Edginton, T.; Bruzzone, M. G.; Giaccone, G. Reviews: Current concepts in Alzheimer's disease: A multidisciplinary review. Am. J. Alzheimers Dis. Other Demen., 2009, 24, 95-121.
7. Aderinwale, O. G.; Ernst, H. W.; Mousa, S. A. Current therapies and new strategies for the management of Alzheimer's disease. Am. J. Alzheimers Dis. Other Demen., 2010, 25, 414-424.
8. Selkoe, D. J. Alzheimer's disease: Genes, proteins and therapy. Physiol. Rev., 2001, 81,741-766. (Pubitemid 32267077)
9. McGeer, P. L.; Schulzer, M.; McGeer, E. G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease. Neurology, 1996, 47, 425-432. (Pubitemid 26324038)
10. Soreq, H.; Seidman, S. Acetylcholinesterase - new roles for an old actor. Nature Rev. Neurosci., 2001, 2, 294-302. (Pubitemid 33673070)
11. Holden, M.; Kelly, C. Use of cholinesterase inhibitors in dementia. Advanc. Psychiat. Treat., 2002, 8, 89-96. (Pubitemid 34213711)
12. Pakaski, M.; Kalman, J. Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease. Neurochem. Inter., 2008, 53, 103-111.
13. Aboukhatwa, M.; Dosanjh, L.; Luo, Y. Antidepressants are a rational complementary therapy for the treatment of Alzheimer's disease. Mol. Neurodegen., 2010, 5, 1-17.
14. Kim, J.; Lee, H. J.; Lee, K. W. Naturally occurring phytochemicals for the prevention of Alzheimer's disease. J. Neurochem., 2010, 112, 1415-1430.
15. Bourne, Y.; Radic, Z.; Kolb, H. C.; Sharpless, K. B.; Taylor, P.; Marchot, P. Structural insights into conformational flexibility at the peripheral site and within the active center gorge of AChE. Chem, Biol. Interact., 2005, 157-158, 159-165. (Pubitemid 41757646)
16. Taylor, P.; Radic, Z. The cholinesterases: From genes to proteins. Annu. Rev. Pharmacol. Toxicol., 1994, 34. 281-320.
17. Massoulie, J.; Pezzementi, L.; Bon, S.; Krejci, E.; Vallette, F. M. Molecular and cellular biology of cholinesterases. Prog. Neurobiol., 1993, 41, 31-91. (Pubitemid 23140755)
18. Shen, T.; Tai, K.; Henchman, R. H.; McCammon, J. A. Molecular dynamics of acetylcholinesterase. Acc. Chem. Res., 2002, 35, 332-340.
19. Dickerson, T. J.; Beuscher IV, A. E.; Rogers, C. J.; Hixon, M. S.; Yamamoto, N.; Xu, Y.; Olson. A. J.; Janda, K. D. Discovery of acetyl cholinesterase peripheral anionic site ligands through computational refinement of a directed library. Biochemistry, 2005, 44, 14845-14853. (Pubitemid 41612264)
20. Harel, M.; Schalk, I.; Ehret-Sabatier, L.; Bouet, F.; Goeldner, M.; Hirrth, C.; Axelsen, P. H.; Silman, I.; Sussman, J. L. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholine esterase. Proc. Natl. Acad. Sci. USA., 1993, 90, 9031-9035. (Pubitemid 23306445)
21. Inestrosa, N. C.; Dinamarca, M. C.; Alvarez, A. Amyloid-cholinesterase interactions - implications for Alzheimer's disease. FEBS., 2008, 275, 625-632. (Pubitemid 351160969)
22. Inestrosa, N. C.; Alvarez, A.; Perez, C. A.; Moreno, R. D.; Vincete, M.; Linker, C.; Casanueva, O. I.; Soto, C.; Garrido, J. Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer's fibrils: Possible role of the peripheral site of the enzyme. Neuron, 1996, 16, 881-891. (Pubitemid 26124065)
23. Belluti, F.; Rampa, A.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Andrisano, V.; Cavalli, A.; Recanatini, M.; Valenti, P. Cholinesterase inhibitors: Xanthostigmine derivatives blocking the acetyl cholinesteraseinduced β-amyloid aggregation. J. Med. Chem., 2005, 48, 4444-4456. (Pubitemid 40884946)
24. Nicolet, Y.; Lockridge, O.; Masson, P.; Fontecilla-Camps, J. C.; Nachon, F. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J. Biol. Chem., 2003, 278, 41141-41147. (Pubitemid 37280939)
25. Greig, N. H.; Utsuki, T.; Ingram, D. K.; Wang, Y.; Pepeu, G.; Scali, C.; Yu, Q.; Mamczarz, J.; Holloway, H. W.; Giordano, T.; Chen, D.; Furukawa, K.; Sambamurti, K.; Brossi, A.; Lahiri, D. K. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent. Proc. Natl. Acad. Sci. USA., 2005, 102, 17213-17218. (Pubitemid 41692709)
26. Darvesh, S.; Hopkins, D. A.; Geula, C. Neurobiology of butyrylcholinesterase. Nature Rev. Neurosci., 2003, 4, 131-138. (Pubitemid 37271383)
27. Vellom, D. C.; Radic, Z.; Li, Y.; Pickering, N. A.; Camp, S.; Taylor, P. Amino acid residues controlling acetylcholinesterase and butyrylcholinesterase specificity. Biochemistry, 1993, 32, 12-17. (Pubitemid 23033314)
28. Saxena, A.; Redman, A. M. G.; Jiang, X.; Lockridge, O.; Doctor, B. P. Differences in active-site gorge dimensions of cholinesterases revealed by binding of inhibitors to human butyrylcholinesterase. Chem. Biol. Interact., 1999, 119-120, 61-69. (Pubitemid 29278539)
29. Camps, P.; Formosa, X.; Galdeano, C.; Gomez, T.; Munzo-Torrero, D.; Scarpellini, M.; Viayna, E.; Badia, A.; Clos, M. V.; Camins, A.; Pallas, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Estelrich, J.; Lizondo, M.; Bidon-Chanal, A.; Luque, F. J. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetyl cholinesterase-induced β-amyloid aggregation. J. Med. Chem., 2008, 51, 3588-3598. (Pubitemid 351875014)
30. Geertsa, H.; Guillaumatb, P.; Granthamc, C.; Bodec, W.; Anciauxc, K.; Sachakd, S. Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits. Brain Res., 2005, 1033, 186-1939.
31. Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V. β-amyloid aggregation induced by human acetylcholinesterase: Inhibition studies. Biochem. Pharmacol., 2003, 65, 407-416. (Pubitemid 36084557)
32. Schrattenholz, A.; Pereira, E. F.; Roth, U.; Weber, K. H.; Albuquerque, E. X.; Maelicke, A. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically active ligands. Mol. Pharmacol., 1996, 49, 1-6. (Pubitemid 26036779)
33. Rainer, M. Clinical studies of galanthamine. Drugs Today, 1997, 4, 273-279.
34. Raskind, M. A.; Peskind, E. R.; Wessel, T.; Yuan, W. Galantamine in AD: A 6-month randomized, placebo-controlled trial a 6-month extension. Neurology, 2000, 54, 2261-2268. (Pubitemid 30416276)
35. Tariot, P. N.; Solomon, P. R.; Morris, J. C.; Kershaw, P.; Lilienfeld, S.; Ding, C. A 5-month, randomized placebo-controlled trial of galantamine in AD. Neurology, 2000, 54, 2269-2276. (Pubitemid 30416277)
36. Coyle, J.; Kershaw, P. Galantamine, the cholinesterase inhibitor that allosterically modulated nicotinic receptors. Biol. Psychiat., 2001, 49, 289-299.
37. Gemma, S.; Gabellieri, E.; Huleatt, P.; Fattorusso, C.; Borriello, M.; Catalanotti, B.; Butini, S.; Angelis, M. D.; Novellino, E.; Nacci, V.; Belinskaya, T.; Saxena, A.; Campiani, G. Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites. J. Med. Chem., 2006, 49, 3421-3425. (Pubitemid 43830542)
38. Li, J.; Wu, H. M.; Zhou, R. L.; Liu, G. J.; Dong, B. R. Huperzine A for Alzheimer's disease. Cochrane Database Syst. Rev., 2005, 2, 1-36.
39. Tang, L. L.; Wang, R.; Tang, X. Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC12 cells. Acta Pharmacol Sin., 2005, 6, 673-678. (Pubitemid 40806555)
40. Ravelli, R. B.; Raves, M. L.; Ren, Z.; Bourgeois, D.; Roth, M.; Kroon, J.; Silman, I.; Sussman, J. L. Static Laue diffraction studies on acetylcholinesterase. Acta Crystallogr., Sect. D, 1998, 54,1359-1366.
41. Melchiorre, C.; Andrisano, V.; Bolognesi, M. L.; Budriesi, R.; Cavalli, A.; Cavrini, V.; Rosini, M.; Tumiatti, V.; Recanatini, M. Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer's disease. J. Med. Chem., 1998, 41, 4186-4189. (Pubitemid 28498739)
42. Yu, Q.; Holloway, H. W.; Flippen-Anderson, J. L.; Hoffman, B.; Brossi, A.; Greig, N. H. Methyl analogues of the experimental Alzheimer drug phenserine: Synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action. J. Med. Chem., 2001, 44, 4062-4071. (Pubitemid 33095315)
43. Klein, J. Phenserine. Expert Opin. Investig. Drugs, 2007, 16, 1087-1097. (Pubitemid 47074163)
44. Geissler, T.; Brandt, W.; Porzel, A.; Schlenzig, D.; Kehlen, A.; Wessjohanna, L.; Arnold, N. Acetylcholinesterase inhibitors from the toadstool Cortinarius infractus. Bioorg. Med. Chem., 2010, 18, 2173-2177.
45. Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner, D.; Goldenberg, W.; Miskolczi, I.; Molnar, S.; Rantal, F.; Tamas, T.; Toth, G.; Zagyva, A.; Zekany, A.; Lavian, G.; Gross, A.; Friedman, R.; Razin, M.; Huang, W.; Krais, B.; Chorev, M.; Youdim, M. B.; Weinstock, M. Novel dual inhibitors of AChE and MAO derived from hydroxyaminoindan and phen-ethylamine as potential treatment for Alzheimer's disease. J. Med. Chem., 2002, 45, 5260-5279. (Pubitemid 35429165)
46. Sauvaitre, T.; Barlier, M.; Herlem, D.; Gresh, N.; Chiaroni, A.; Geunard. D.; Guillou, C. New potent acetylcholinesterase inhibitors in the tetracyclic triterpene series. J. Med. Chem., 2007, 50, 5311-5323. (Pubitemid 350057843)
47. Watkins, P. B.; Zimmerman, H. J.; Knapp, M. J.; Gracon, S. I.; Lewis, K. W. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA, 1994, 271, 992-998. (Pubitemid 24099919)
48. Villalobos, A.; Blake, J. F.; Biggers, C. K.; Butler, T. W.; Chapin, D. S.; Chen, Y. L.; Ives, J. L.; Jones, S. B.; Liston, D. R.; Nagel, A. A.; Nason, D. M.; Nielsen, J. A.; Shalaby, I. A.; White, W. F. Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase. J. Med. Chem., 1994, 37, 2721-2734. (Pubitemid 24273464)
49. Butini, S.; Guarino, E.; Campiani, G.; Brindisi, M.; Coccone, S. S.; Fiorini, I.; Novellino, E.; Belinskaya, T.; Saxena, A.; Gemma, S. Tacrine based human cholinesterase inhibitors: Synthesis of peptidic-tethered derivatives and their effect on potency and selectivity. Bioorg. Med. Chem. Lett., 2008, 18, 5213-5216.
50. Kamal, M. A.; Qu, X.; Yu, Q.; Tweedie, D.; Holloway, H. W.; Li, Y.; Tan, Y.; Greig, N. H. Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis. J. Neural. Transm., 2008, 115, 889-898.
51. Carolan, C. G.; Dillon, G. P.; Khan, D.; Ryder, S. A.; Gaynor, J. M.; Reidy, S.; Marquez, J. F.; Jones, M.; Holland, V.; Gilmer, J. F. Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor. J. Med. Chem., 2010, 53, 1190-1199.
52. Mohamed, T.; Zhao, X.; Habib, L. K.; Yang, J.; Rao, P. P. N. Design, synthesis and structure-activity relationship (SAR) studies of 2,4-disubstituted pyrimidine derivatives: Dual activity as cholinesterase and Aβ-aggregation inhibitors. Bioorg. Med. Chem., 2011, 19, 2269-2281.
53. Pang, Y.; Quiram, P.; Jelacic, T.; Hong, F.; Brimijoin, S. Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. J. Biol. Chem., 1996, 271, 23646-23649.
54. Carlier, P. R.; Du, D.; Han, Y.; Liu, J.; Perola, E.; Williams, I. D.; Pang, Y. Dimerization of an inactive fragment of huperzine A produces a drug with twice the potency of the natural product. Agnew. Chem. Int. Ed., 2000, 39, 1775-1777. (Pubitemid 30365754)
55. Guillou, C.; Mary, A.; Renko, D. Z.; Gras, E.; Thal, C. Potent acetylcholinesterase inhibitors: Design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthaminegalanthaminium salts. Bioorg. Med. Chem. Lett., 2000, 10, 637-639. (Pubitemid 30186667)
56. Greenbaltt, H. M.; Guillou, C.; Guenard, D.; Argaman, A.; Botti, S.; Badet, B.; Thal, C.; Silman, I.; Sussman, J. L. The complex of a bivalent derivative with galanthamine with Torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: Implications for structure-based drug design. J. Am. Chem. Soc., 2004, 126, 15405-15411. (Pubitemid 39577474)
57. Campiani, G.; Fattorusso, C.;Butini, S.; Gaeta, A.; Agnusdei, M.; Gemma, S.; Persico, M.; Catalanotti, B.; Savini, L.; Nacci, V.; Novellino, E.; Holloway, H. W.; Greig, N. H.; Belinskaya, T.; Fedorko, J. M.; Saxena, A. Development of molecular probes for the identification of extra interaction sites in the mid-gorge and peripheral sites of butyrylcholinesterase (BuChE). Rational design of novel, selective, and highly potent BuChE inhibitors. J. Med. Chem., 2005, 48, 1919-1929. (Pubitemid 40396322)
58. Butini, S.; Campiani, G.; Borriello, M.; Gemma, S.; Panico, A.; Perisco, M.; Catalanotti, B.; Ros, S.;Brindisi, M.; Agnusdei, M.; Fiorini, I.; Nacci, V.; Novellino, E.; Belinskaya, T.; Saxena, A.; Fattorusso, C. Exploiting protein fluctuations at the active-site gorge of human cholinesterases: Further optimization of the design strategy to develop extremely potent inhibitors. J. Med. Chem., 2008, 51, 3154-3170. (Pubitemid 351821876)
59. Leonetti, F.; Catto, M.; Nicolotti, O.; Pisani, L.; Cappa, A.; Stefanachi, A.; Carotti, A. Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors. Bioorg. Med. Chem., 2008, 16, 7450-7456.
60. Decker, M. Homobivalent quinazolinimines as novel nanomolar inhibitors of cholinesterases with dirigible selectivity toward butyryl -cholinesterase. J. Med. Chem., 2006, 49, 5411-5413. (Pubitemid 44373174)
61. Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Banzi, R.; Melchiorre, C. Propidium-based polyamine ligands as potent inhibitors of acetylcholinesterase and acetyl-cholinesterase-induced amyloid-β aggregation. J. Med. Chem., 2005, 48, 24-27. (Pubitemid 40105245)
62. Rodriguez-Franco, M. I.; Fernandez -Bachiller, M. I.; Perez, C.; Hernandez-Ledesma, B.; Bartolome, B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and anti-oxidant properties. J. Med. Chem., 2006, 49, 459-462. (Pubitemid 43157478)
63. Weinbroum, A. A. Pathophysiological and clinical aspects of combat anticholinesterase poisoning. Br. Med. Bull., 2004, 72, 119-133. (Pubitemid 40712662)
64. Jensen, A. A.; Frølund, B.; Liljefors, T.; Krogsgaard-Larsen, P. Neuronal nicotinic acetylcholine receptors: Structural revelations, target identifications, and therapeutic inspirations. J. Med. Chem., 2005, 48, 4705-4745. (Pubitemid 41038456)
65. Mullen, G.; Napier, J.; Balestra, M.; DeCory, T.; Hale, G.; Macor, J.; Mack, R.; Loch III, J.; Wu, E.; Kover, A.; Verhoest, P.; Sampognaro, A.; Phillips, E.; Zhu, Y.; Murray, R.; Griffith, R.; Blosser, J.; Gurley, D.; Machulskis, A.; Zongrone, J.; Rosen, A.; Gordon, J. (-)-Spiro[1-azabicyclo[2.2. 2]octane-3,5α-oxazolidin-2β-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the β7 nicotinic acetylcholine receptor. J. Med. Chem., 2000, 43, 4045-4050.
66. Tatsumi, R.; Fujio, M.; Satoh, H.; Katayama, J.; Takanashi, S.; Hashimoto, K.; Tanaka, H. Discovery of the α7 nicotinic acetylcholine receptor agonists. (R)-3′-(5-Chlorothiophen-2-yl) spiro-1-azabicyclo[2.2. 2]octane-3,5′-[1′,3′]-oxazolidin-2′-one as a novel, potent, selective, and orally bioavailable ligand. J. Med. Chem., 2005, 48, 2678-2686. (Pubitemid 40516457)
67. Bunnelle, W. H.; Daanen, J. F.; Ryther, K. B.; Schrimpf, M. R.; Dart, M. J.; Gelain, A.; Meyer, M. D.; Frost, J. M.; Anderson, D. J.; Buckley, M.; Curzon, P.; Cao, Y.; Puttfarcken, P.; Searle, X.; Ji, J.; Putman, C. B.; Surowy, C.; Toma, L.; Barlocco, D. Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors. J. Med. Chem., 2007, 50, 3627-3644. (Pubitemid 47201814)
68. Bunnelle, W. H.; Tietje, K. R.; Frost, J. M.; Peters, D.; Ji, J.; Li, T.; Scanio, M. J. C.; Shi, L.; Anderson, D. J.; Dyhring, T.; Grønlien, J. H.; Ween, H.; Thorin-Hagene, K.; Meyer, M. D. Octahydropyr-rolo[3,4-c]pyrrole: A diamine scaffold for construction of either α4β2 or α7-selective nicotinic acetylcholine receptor (nAChR) ligands. Substitutions that switch subtype selectivity. J. Med. Chem., 2009, 52, 4126-4141.
69. Davis, A. A.; Heilman, C. J.; Brady, A. E.; Miller, N. R.; Fuerstenau-sharp, M.; Hanson, B. J.; Lindsley, C. W.; Conn, P. J.; Lah, J. J.; Levey, A. I. Differential effects of allosteric M1 muscarinic acetylcholine receptor agonists on receptor activation, arrestin 3 recruitment, and receptor downregulation. ACS Chem. Neurosci., 2010, 1, 541-551.
70. Lebois, E. P.; Bridges, T. M.; Lewis, L. M.; Dawson, E. S.; Kane, A. S.; Xiang, Z.; Jadhav, S. B.; Yin, H.; Kennedy, J. P.; Meiler, J.; Niswender, C. M.; Jones, C. K.; Conn, P. J.; Weaver, C. D.; Lindsley, C. W. Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M1 receptor function in the central nervous system. ACS Chem. Neurosci., 2010, 1, 104-121.
71. Sams, A. G.; Hentzer, M.; Mikkelsen, G. K.; Larsen, K.; Bundgaard, C.; Plath, N.; Christoffersen, C. T.; Bang-Andersen, B. Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxa zin-4-yl)propyl]piperidin-4-yl}-2-phenyl acetamide (Lu AE51090): An allosteric muscarinic M1 receptor agonist with unprecedented selectivity and precognitive potential. J. Med. Chem., 2010, 53, 6386-6397.
72. Hardy, J.; Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharm. Sci., 1991, 12, 383-388.
73. Selkoe, D. J. The molecular pathology of Alzheimer's disease. Neuron 1991, 6, 487-498.
74. Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science, 2002, 297, 353-356. (Pubitemid 34790756)
75. Dinamarca, M. C.; Sagal, J. P.; Quintanilla, R. A.; Godoy, J. A.; Arrazola, M. S.; Inestrosa, N. C. Amyloid-β-acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Aβ peptide. Implications for the pathogenesis of Alzheimer's disease. Mol. Neurodegener., 2010, 5, 2-15.
76. Rosini, M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.; McClymont, D. W.; Tarozzi, A.; Bolognesi, M. L.; Minarini, A.; Tumiatti, V.; Andrisano, V.; Mellor, I. R.; Melchiorre, C. Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA receptors in Alzheimer's disease: A promising direction for the multi-target-directed ligands gold rush J. Med. Chem., 2008, 51, 4381-4384.
77. Priller, C.; Bauer, T.; Mitteregger, G.; Krebs, B.; Kretzschmar, H. A.; Herms, J. Synapse formation and function is modulated by the amyloid precursor protein. J. Neurosci., 2006, 26, 7212-7221.
78. Zheng, H.; Koo, E. H. The amyloid precursor protein: Beyond amyloid. Mol. Neurodegener., 2006, 1, 5-16.
79. Suh, Y.; Checler, F. Amyloid precursor protein, presenilins, and α-synuclein: Molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol. Rev., 2002, 54, 469-525.
80. Cerpa, W. F.; Barria, M. I.; Chacon, M. A.; Suazo, M.; Gonzalez, M.; Opazo, C.; Bush, A. I.; Inestrosa, N. C. The N-terminal copper-binding domain of the amyloid precursor protein protects against Cu2+ neurotoxicity in vivo. FASEB J., 2004, 18, 1701-1703. (Pubitemid 39561656)
81. Racchi, M.; Mazzucchelli, M.; Lenzken, S. C.; Porrello, E.; Lanni, C.; Govoni, S. Role of acetylcholinesterase inhibitors in the regulation of amyloid β precursor protein (AβPP) metabolism. Chem. Biol. Interact., 2005, 157-158, 335-338. (Pubitemid 41757671)
82. Parvathy, S.; Hussain, I.; Karran, E. H.; Turner, A. J.; Hooper, N. M. Cleavage of Alzheimer's amyloid precursor protein by α-secretase occurs at the surface of neuronal cells. Biochemistry, 1999, 38, 9728-9734.
83. Lichtenthaler, S. F.; Haass, C. Amyloid at the cutting edge: Activation of α-secretase prevents amyloidogenesis in an Alzheimer's disease mouse model. J. Clin. Investig., 2004, 113, 1384-1387. (Pubitemid 39071692)
84. Hemming, M. L.; Elias, J. E.; Gygi, S. P.; Selkoe, D. J. Identification of β-secretase (BACE1) substrates using quantitative proteomics. PLoS ONE, 2009, 4, e8477.
85. Citron, M. β-Secretase inhibition for the treatment of Alzheimer's disease - promise and challenge. Trends Pharm. Sci., 2004, 25, 92-97. (Pubitemid 38183395)
86. Skovronsky, D. M.; Lee, V. M-Y. β-Secretase revealed: Starting gate for race to novel therapies for Alzheimer's disease. Trends Pharm. Sci., 2000, 21, 161-163. (Pubitemid 30243192)
87. Zhou, S.; Zhou, H.; Walian, P. J.; Jap, B. K. Regulation of γ-secretase activity in Alzheimer's disease. Biochemistry, 2007, 46, 2553-2563. (Pubitemid 46417899)
88. Fraering, P. C.; Ye, W.; LaVoie, M. J.; Ostaszewski, B. L.; Selkoe, D. J.; Wolfe, M. S. γ-secretase substrate specificity can be modulated directly via interaction with a nucleotide-binding site. J. Biol. Chem., 2005, 280, 41987-41996. (Pubitemid 43023167)
89. Wolfe, M. S. The γ-secretase complex: Membrane-embedded proteolytic ensemble. Biochemistry, 2006, 45, 7931-7939. (Pubitemid 43993216)
90. Raurell, I.; Codina, M.; Casagolda, D.; Valle, B.; Baulida, J.; Herreros, A. G.; Dunach, M. Gamma-secretase-dependant and independent effects of presenilin1 on β-catenin.Tcf-4 transcriptional activity. PLoS ONE, 2008, 3, e4080.
91. Small, D. H.; Klaver, D. W.; Foa, L. Presenilins and the γ-secretase: Still a complex problem. Mol. Brain, 2010, 3, 7-12.
92. Beel, A. J.; Barrett, P.; Schnier, P. D.; Hitchcock, S. A.; Bagal, D.; Sanders, C. R.; Jordan, J. B. Nonspecificity of binding of γ-secretase modulators to the amyloid precursor protein. Biochemistry, 2003, 48, 11837-11839.
93. Ghosh, A. K.; Bilcer, G.; Harwood, C.; Kawahama, R.; Shin, D.; Hussain, K. A.; Hong, L.; Loy, J. A.; Nguyen, C.; Koelsch, G.; Ermolieff, J.; Tang, J. Structure-based design: Potent inhibitors of human brain memapsin-2 (β-secretase). J. Med. Chem., 2001, 44, 2865-2868. (Pubitemid 32879115)
94. Hanessian, S.; Shao, Z.; Betschart, C.; Rondeau, J.; Neumann, U.; Tintelnot-Blomley, M. Sructure-based design and synthesis of novel P2/P3 modified, non-peptidic β-secretase (BACE-1) inhibitors. Bioorg. Med. Chem. Lett., 2010, 20, 1924-1927.
95. Garino, C.; Tomita, T.; Pietrancosta, N.; Laras, Y.; Rosas, R.; Herbette, G.; Maigret, B.; Quelever, G.; Iwatsubo, T.; Kraus, J. Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human β-secretase inhibitors. Design, synthesis and enzymatic BACE-1 and cell assays. J. Med. Chem., 2006, 49, 4275-4285. (Pubitemid 44036671)
96. Malamas, M. S.; Barnes, K.; Hui, Y.; Johnson, M.; Lovering, F.; Condon, J.; Fobare, W.; Solvibile, W.; Turner, J.; Hu, Y.; Manas, E. S.; Fan, K.; Olland, A.; Chopra, R.; Bard, J.; Pangalos, M. N.; Reinhart, P.; Robichaud, A. J. Novel pyrrolyl-2-aminopyridines as potent and selective human β-secretase (BACE-1) inhibitors. Bioorg. Med. Chem. Lett., 2010, 20, 2068-2073.
97. Gillman, K. W.; Starrett Jr., J. E.; Parker, M. F.; Xie, K.; Bronson, J. J.; Marcin, L. R.; McElhone, K. E.; Bergstrom, C. P.; Mate, R. A.; Williams, R.; Meredith Jr., J. E.; Burton, C. R.; Barten, D. M.; Toyn, J. H.; Roberts, S. B.; Lentz, K. A.; Houston, J. G.; Zaczek, R.; Albright, C. F.; Decicco, C. P.; Macor, J. E.; Olson, R. E. Discovery and evaluation of BMS-70816, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med. Chem. Lett., 2010, 1, 120-124.
98. Hieke, M.; Ness, J.; Steri, R.; Dittrich, M.; Greiner, C.; Werz, O.; Baumann, K.; Schubert-Zsilavecz, M.; Weggen, S.; Zettl, H. Design, synthesis and biological evaluation of a novel class of γ-secretase modulators with PPARγ activity. J. Med. Chem., 2010, 53, 4691-4700.
99. Shelton, C. C.; Zhu, L.; Chau, D.; Yang, L.; Wang, R.; Djaballah, H.; Zheng, H.; Li, Y. Modulation of γ-secretase specificity using small molecule allosteric inhibitors. Proc. Natl. Acad. Sci. USA, 2009, 106, 20228-20233.
100. Karr, J. W.; Akintoye, H.; Kaupp, L. J.; Szalai, V. A. N-terminal deletions modify the Cu2+ binding site in amyloid-β. Biochemistry, 2005, 44, 5478-5487. (Pubitemid 40489987)
101. Chen, T.; Wang, X.; He, Y.; Zhang, C.; Wu, Z.; Liao, K; Wang, J.; Guo, Z. Effects of cyclen and cyclam on zinc(II)- and copper(II)-induced amyloid β-peptide aggregation and neurotoxicity. Inorg. Chem., 2009, 48, 5801-5809.
102. 2+ induced aggregation and dityrosine formation of the Alzheimer's disease amyloid-β peptide. Biochemistry, 2007, 46, 2881-2891. (Pubitemid 46417926)
103. Nakamura, M.; Shishido, N.; Nunomura, A.; Smith, M. A.; Perry, G.; Hayashi, Y.; Nakayama, K.; Hayashi, T. Three histidine residues of amyloid-β peptide control the redox activity of copper and iron. Biochemistry, 2007, 46, 12737-12743. (Pubitemid 350064223)
104. Sarell, C. J.; Syme, C. D.; Rigby, S. E. J.; Viles, J. H. Copper(II) binding to amyloid-β fibrils of Alzheimer's disease reveals a picomolar affinity: Stoichiometry and coordination geometry are independent of Aβ oligomeric form. Biochemistry, 2009, 48, 4388-4402.
105. Ha, C.; Ryu, J.; Park, C. B. Metal ions differentially influence the aggregation and deposition of Alzheimer's βs-amyloid on a solid template. Biochemistry, 2007, 46, 6118-6125. (Pubitemid 46799170)
106. Scott, L. E.; Orvig, C. Medicinal inorganic chemistry approaches to passivation and removal of aberrant metal ions in disease. Chem. Rev., 2009, 109, 4885-4910.
107. Zatta, P.; Drago, D.; Bolognin, S.; Sensi, S. L. Alzheimer's disease, metal ions and metal homeostatic therapy. Trends Pharm. Sci., 2009, 30, 346-355.
108. Zhou, Y.; Jiang, C.; Zhang, Y.; Liang, Z.; Liu, W.; Wang, L.; Luo, C.; Zhong, T.; Sun, Y.; Zhao, L.; Xie, X.; Jiang, H.; Zhou, N.; Liu, D.; Liu, H. Structural optimization and biological evaluation of substituted bisphenol A derivatives as β-amyloid peptide aggregation inhibitors. J. Med. Chem., 2010, 53, 5449-5466.
109. Camps, P.; Formosa, X.; Galdeano, C.; Munoz-Torrero, D.; Ramirez, L.; Gomez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M. V.; Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M. P.; Rodrigues-Franco, M. I.; Huertas, O.; Dafni, T.; Luque, F. J. Pyrano[3,2-c]quinoline-6-chloro-tacrine hybrids as a novel family of acetylcholinesterase and β-amyloid-directed anti-Alzheimer's compounds. J. Med. Chem., 2009, 52, 5365-5379.
110. Arce, M. P.; Rodrigues-Franco, M. I.; Gonzalez-Munoz, G. C.; Perez, C.; Lopez, B.; Villarroya, M.; Lopez, M. G.; Garcia, A. G.; Conde, S. Neuroprotective and cholinergic properties of multifunctional glutamic acid derivatives for the treatment of Alzheimer's disease. J. Med. Chem., 2009, 52, 7249-7257.
111. Cherny, R. A.; Atwood, C. S.; Xilinas, M. E.; Gray, D. N.; Jones, W. D.; McLean, C. A.; Barnham, K. J.; Volitakis, I.; Fraser, F. W.; Kim, Y.; Huang, X.; Goldstein, L. E.; Moir, R. D.; Lim, J. T.; Beyreuther, K.; Zheng, H.; Tanzi, R. E.; Masters, C. L.; Bush, A. I. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mouse. Neuron, 2001, 30, 665-676. (Pubitemid 32607332)
112. Deraeve, C.; Pitie, M.; Mazarguil, H.; Meunier, B. Bis-8-hydroxyquinoline ligands as potential anti-Alzheimer agents. New J. Chem., 2007, 31, 193-195. (Pubitemid 46227045)
113. Deraeve, C.; Maraval, A.; Vendier, L.; Faugeroux, V.; Pitie, M.; Meunier, B. Preparation of new bis(8-aminoquinoline) ligands and comparison with bis(8-hydroxy quinoline) ligands on their ability to chelate CuII and ZnII. Eur. J. Inorg. Chem., 2008, 5622-5631.
114. Fernandez-Bachiller, M. I.; Perez, C.; Gonzalez-Munoz, G. C.; Conde, S.; Lopez, M. G.; Villarroya, M.; Garcia, A. G.; Rodriguez-Franco, M. I. Novel tacrine-8-hydroxy quinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease with neuro protective, cholinergic, antioxidant and copper-complexing properties. J. Med. Chem., 2010, 53, 4927-4937.
115. Yang, L. X.; Huang, K. X.; Li, H. B.; Gong, J. X.; Wang, F.; Feng, Y. B.; Tao, Q. F.; Wu, Y. H.; Li, X. K.; Wu, X. M.; Zeng, S.; Spencer, S.; Zhao, Y.; Qu, J. Design, synthesis and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives. J. Med. Chem., 2009, 52, 7732-7752.
116. Castellani, R. J.; Rolston, R. K.; Smith, M. A. Alzheimer's disease. Dis. Mon. 2010, 56, 484-546.
117. Metcalfe, M. J.; Figueiredo-Pereira, M. E. Relationship between tau pathology and neuroinflammation in Alzheimer's disease. Mt. Sinai J. Med., 2010, 77, 50-58.
118. Felician, O.; Sandson, T. A. The neurobiology and pharmacotherapy of Alzheimer's disease. J. Neuropsychiat., 1999, 11, 19-31. (Pubitemid 29070660)
119. Gendron, T. F.; Petrucelli, L. The role of tau in neurodegeneration. Mol. Neurodegen., 2009, 4, 13-31.
120. Avila, J.; Lucas, J. J.; Perez, M.; Hernandez, F. Role of tau protein in both physiological and pathological conditions. Physiol. Rev., 2004, 84, 361-384. (Pubitemid 38365487)
121. Brunden, K. R.; Trojanowski, J. Q.; Lee, V. M-Y. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nature Rev. Drug Dis., 2009, 8, 783-793.
122. Francis, P. T.; Ramirez, M. J.; Lai, M. K. Neurochemical basis for symptomatic treatment of Alzheimer's disease. Neuropharmacol., 2010, 59, 221-229.
123. Proctor, C. J.; Gray, D. A. GSK3 and p53 - is there a link in Alzheimer's disease? Mol. Neurodegen., 2010, 5, 7-21.
124. Cruz, J. C.; Tseng, H.; Goldman, J. A.; Shih, H.; Tsai, L. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron, 2003, 40, 471-483. (Pubitemid 37494698)
125. Liu, M.; Choi, S.; Cuny, G. D.; Ding, K.; Dobson, B. C.; Glicksman, M. A.; Auerbach, K.; Stein, R. L. Kinetic studies of Cdk5/p25 kinase: Phosphorylation of tau and complex inhibition by two prototype inhibitors. Biochemistry, 2008, 47, 8367-8377.
126. Li, T.; Paudel, H. K. Glycogen synthase kinase 3β phosphorylates Alzheimer's disease-specific Ser396 of microtubule-associated protein tau by a sequential mechanism. Biochemistry, 2006, 45, 3125-3133. (Pubitemid 43376331)
127. Li, T.; Hawkes, C.; Qureshi, H. Y.; Kar, S.; Paudel, H. K. Cyclin-dependent protein kinase 5 primes microtubule-associated tau site-specifically for glycogen synthase kinase 3β. Biochemistry, 2006, 45, 3134-3145. (Pubitemid 43376332)
128. Oumata, N.; Bettayeb, K.; Ferandin, Y.; Demange, L.; Lopez-Giral, A.; Goddard, M.; Myrianthopoulos, V.; Mikros, E.; Flajolet, M.; Greengard, P.; Meijer, L.; Galons, H. Roscovitine-derived, dual specificity inhibitors of cyclin-dependant kinases and casein kinases 1. J. Med. Chem., 2008, 51, 5229-5242.
129. Saitoh, M.; Kunitomo, J.; Kimura, E.; Iwashita, H.; Uno, Y.; Onishi, T.; Uchiyama, N.; Kawamoto, T.; Tanaka, T.; Mol, C. D.; Dougan, D. R.; Textor, G. P.; Snell, G. P.; Takizawa, M.; Itoh, F.; Kori, M. 2-{3-[4-(Alkylsulfinyl)
130. Chang, E.; Congdon, E. E.; Honson, N. S.; Duff, K. E.; Kuret, J. Structureactivity relationship of cyanine tau aggregation inhibitors. J. Med. Chem., 2009, 52, 3539-3547.
131. Ballatore, C.; Brunden, K. R.; Piscitelli, F.; James, J. M.; Crowe, A.; Yao, Y.; Hyde, E.; Trojanowski, J. Q.; Lee, V. M-Y.; Smith III, A. B. Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation. J. Med. Chem., 2010, 53, 3739-3747.
132. Hoey, S. E.; Williams, R. J.; Perkinton, M. S. Synaptic NMDA receptor activation stimulates α-secretase amyloid precursor protein processing and inhibits amyloid-β production. J. Neurosci., 2009, 29, 4442-4460.
133. Kemp, J. A.; McKernan, R. M. NMDA receptor pathways as drug targets. Nature Neurosci., 2002, 5, 1039-1042. (Pubitemid 35247194)
134. Schelkun, R. M.; Yuen, P.; Serpa, K.; Meltzer, L. T.; Wise, L. D. Subtypeselective N-Methyl-D-aspartate receptor antagonists: Benzimidazalone and hydantoin as phenol replacements. J. Med. Chem., 2000, 43, 1892-1897. (Pubitemid 30305022)
135. Sonkusare, S. K.; Kaul, C. L.; Ramarao, P. Dementia of Alzheimer's disease and other neurodegenerative disorders - memantine, a new hope. Pharmacol. Res., 2005, 51, 1-17. (Pubitemid 39425068)
136. Ray, B.; Banerjee, P. K.; Greig, N. H.; Lahiri, D. K. Memantine treatment decreases levels of secreted Alzheimer's amyloid precursor protein (APP) and amyloid beta (Aβ) peptide in the human neuroblastoma cells. Neurosci. Lett., 2010, 470, 1-5.
137. Chohan, M. O.; Iqbal, K. From tau to toxicity: Emerging roles of NMDA receptor in Alzheimer's disease. J. Alz. Dis., 2006, 10, 81-87. (Pubitemid 44401369)
138. Rosini, M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.; McClymont, D. W.; Tarozzi, A.; Bolognesi, M. L.; Minarini, A.; Tumiatti, V.; Andrisano, V.; Mellor, I. R.; Melchiorre, C. Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA receptors in Alzheimer's disease: A promising direction for the multi-target-directed ligands gold rush. J. Med. Chem., 2008, 51, 4381-4384.
139. Mosley, C. A.; Myers, S. J.; Murray, E. E.; Santangelo, R.; Tahirovic, Y. A.; Kurtkaya, N.; Mullasseril, P.; Yuan, H.; Lyuboslavsky, P.; Le, P.; Wilson, L. J.; Yepes, M.; Dingledine, R.; Traynelis, S. F.; Liotta, D. C. Synthesis, structural-activity relationships, and biological evaluation of novel amidebased allosteric binding site antagonists in NR1A/NR1B N-methyl-Daspartate receptors. Bioorg. Med. Chem., 2009, 17, 6463-6480.
140. Sayre, L. M.; Perry, G.; Smith, M. A. Oxidative stress and neurotoxicity. Chem. Res. Toxicol., 2008, 21, 172-188. (Pubitemid 351219718)
141. Pratico, D. Oxidative stress hypothesis in Alzheimer's disease: A reappraisal. Trends Pharmacol. Sci., 2008, 29, 609-615.
142. Zatta, P.; Drago, D.; Bolognin, S.; Sensi, S. L. Alzheimer's disease, metal ions and metal homeostatic therapy. Trends Pharmacol. Sci., 2009, 30, 346-355.
143. Brewer, G. J. Risks of copper and iron toxicity during aging in humans. Chem. Res. Toxicol., 2010, 23, 319-326.
144. Jin, H.; Randazzo, J.; Zhang, P.; Kador, P. F. Multifunctional antioxidants for the treatment of age-related diseases. J. Med. Chem., 2010, 53, 1117-1127.
145. Zheng, H.; Youdim, M. B. H.; Fridkin, M. Selective acetylcholinesterase inhibitor activated by acetylcholinesterase releases an active chelator with neurorescuing and anti-amyloid activities. ACS Chem. Neurosci., 2010, 1, 737-746.
146. Frank-Cannon, T. C.; Alto, L. T.; McAlpine, F. E.; Tansey, M. G. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol. Neurodegen., 2009, 4, 47-59.
147. Medeiros, R.; Figueiredo, C. P.; Pandolfo, P.; Duarte, F. S.; Prediger, R. D. S.; Passos, G. F.; Calixto, J. B. The role of TNF-α signaling pathway on COX-2 upregulation and cognitive decline induced by β-amyloid peptide. Behaviour. Brain Res., 2010, 209, 165-173.
148. Pratico, D.; Zhukareva, V.; Yao, Y.; Uryu, K.; Funk, C. D.; Lawson, J. A.; Trojanowski, J. Q.; Lee, V. M-Y. 12/15-lipooxygenase is increased in Alzheimer's disease. Am. J. Pathol., 2004, 164, 1655-1662.
149. Tobinick, E. L.; Gross, H. Rapid cognitive improvement in Alzheimer's disease following peri-spinal etanercept administration. J. Neuroinflamm., 2008, 5, 2-11.
150. McGeer, P. L.; Rogers, J.; McGeer, E. G. Inflammation, anti-inflammatory agents and Alzheimer's disease: The last 12 years. J. Alz. Dis., 2006, 9, 271-276. (Pubitemid 44253320)
151. 1-42 secretion. J. Med. Chem., 2005, 48, 5705-5720. (Pubitemid 41298345)
152. Bortolato, M.; Chen, K.; Shih, J. C. Monoamine oxidase inactivation: From pathophysiology to therapeutics. Adv. Drug Deliv. Rev., 2008, 60, 1527-1533.
153. Yamada, M.; Yasuhara, H. Clinical pharmacology of MAO inhibitors: Safety and future. Neurotoxiocol., 2004, 25, 215-221. (Pubitemid 38044183)
154. Gokhan-Kelekci, N.; Yabanoglu, S.; Kupeli, E.; Salgin, U.; Ozgen, O.; Ucar, G.; Yesilada, E.; Kendi, E.; Yesilada, A.; Bilgin, A. A. A new therapeutic approach in Alzheimer's disease: Some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics. Bioorg. Med. Chem., 2007, 15, 5775-5786. (Pubitemid 47043476)
155. Bruhlmann, C.; Ooms, F.; Carrupt, P.; Testa, B.; Catto, M.; Leonetti, F.; Altomare, C.; Carotti, A. Coumarin derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase. J. Med. Chem., 2001, 44, 3195-3198. (Pubitemid 32862350)
156. Youdim, M. B. H.; Edmondson, D.; Tipton, K. F. The therapeutic potential of monoamine oxidase inhibitors. Nature Rev. Neurosci., 2006, 7, 295-309.
157. Aboukhatwa, M.; Dosanjh, L.; Luo, Y. Antidepressants are a rational complementary therapy for Alzheimer's disease. Mol. Neurodegen., 2010, 5, 10-27.
158. Steen, E.; Terry, B. M.; Rivera, E. J.; Cannon, J. L.; Neely, T. R.; Tavares, R.; Xu, X. J.; Wands, J. R.; Monte, S. M. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease - is this type 3 diabetes? J. Alzheimer's Dis., 2005, 7, 63-80. (Pubitemid 40387185)
159. Zhu, X.; Perry, G.; Smith, M. A. Insulin signaling, diabetes mellitus and risk of Alzheimer's disease. J. Alzheimer's Dis., 2005, 7, 81-84. (Pubitemid 40387186)
160. Monte, S. M.; Tong, M.; Lester-Coll, N.; Plater Jr., M.; Wands, J. R. Therapeutic rescue of neuro-degeneration in experimental type 3 diabetes: Relevance to Alzheimer's disease. J. Alzheimer's Dis., 2006, 10, 89-109. (Pubitemid 44401370)
161. Monte, S. M.; Wands, J. R. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer's disease. J. Alzheimer's Dis., 2005, 7, 45-61. (Pubitemid 40387184)
162. Jones, A.; Kulozik, P.; Ostertag, A.; Herzig, S. Common pathological processes and transcriptional pathways in Alzheimer's disease and type 2 diabetes. J. Alzheimer's Dis., 2009, 16, 787-808.
163. Granic, I.; Dolga, A. M.; Nijholt, I. M.; Dijk, G. V.; Eisel, U. L. M. Inflammation and NF-βB in Alzheimer's disease and diabetes. J. Alzheimer's Dis., 2009, 16, 809-821.
164. Extance, A. Alzheimer's failure raises questions about disease-modifying strategies. Nature Rev. Drug Disc., 2010, 9, 749-751.
165. Melnikova, I. Therapies for Alzheimer's disease. Nature Rev. Drug Disc., 2007, 6, 341-342. (Pubitemid 46696548)
166. Morimoto, B. H.; Lannoy, I. D.; Fox, A. W.; Gozes, I.; Stewart, A. Davunetide - Pharmacokinetics and distribution to brain after intravenous or intranasal administration to rat. Chem. Today, 2009, 27, 16-20.
167. Bolognesi, M. L.; Bartolini, M.; Rosini, M.; Andrisano, V.; Melchiorre, C. Structure-activity relationships of memoquin: Influence of the chain chirality in the multi-target mechanism of action. Bioorg. Med. Chem. Lett., 2009, 19, 4312-4315.
168. Bolognesi, M. L.; Cavalli, A.; Melchiorre, C. Memoquin: A multi-targetdirected ligand as an innovative therapeutic opportunity for Alzheimer's disease. Neurotherapeutics, 2009, 6, 152-162.
169. Mangialasche, F.; Solomon, A.; Winbald, B.; Mecocci, P.; Kivipelto, M. Alzheimer's disease: Clinical trials and drug development. Lancet Neurol., 2010, 9, 702-716.
170. Noble, W.; Garwood, C.; Stephenson, J.; Kinsey, A. M.; Hanger, D. P.; Anderton, B. H. Minocycline reduces the development of abnormal tau species in models of Alzheimer's disease. FASEB J., 2009, 23, 739-750.
171. Pogacic, V.; Herrling, P. List of drugs in development for neurodegenerative diseases. Neurodegen. Dis., 2007, 4, 443-486.
172. Amijee, H.; Scopes, D. I. The quest for small molecules as amyloid inhibiting therapies for Alzheimer's disease. J. Alzheimer's Dis., 2009, 17, 33-47.
173. Weinreb, O.; Mandel, S.; Bar-Am, O.; Yogev-Falach, M.; Avramovich-Tirosh, Y.; Amit, T.; Youdim, M. B. H. Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer's disease drugs. Neurotherap., 2009, 6, 163-174.
174. Necula, M.; Chirita, C. N.; Kuret, J. Cyanine dye N-744 inhibits tau fibrillization by blocking filament extension: Implications for the treatment of tauopathic neurodegenerative diseases. Biochemistry, 2005, 44, 10227, 10237.
175. Wisniewski, T.; Konietzko, U. Amyloid-β immunization for Alzheimer's disease. Lancet Neurol., 2008, 7, 805-811.