Progress and developments in tau aggregation inhibitors for Alzheimer disease

Journal of Medicinal Chemistry

Volumn 56, Issue 11, 2013, Pages 4135-4155

  Bulic, Bruno ^a   Pickhardt, Marcus ^b   Mandelkow, Eckhard ^b,c,d  

^a HUMBOLDT UNIVERSITY   (Germany)

^b GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^c CENTER OF ADVANCED EUROPEAN STUDIES AND RESEARCH CAESAR   (Germany)

^d MAX PLANCK INSTITUTE FOR NEUROLOGICAL RESEARCH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANILINE DERIVATIVE; ANTHRAQUINONE DERIVATIVE; BENZOTHIAZOLE DERIVATIVE; HYDANTOIN DERIVATIVE; OLIGOMER; POLYPHENOL; PROTEIN INHIBITOR; PYRIDAZINE DERIVATIVE; RHODANINE; TAU AGGREGATION INHIBITOR; TAU PROTEIN; THIOHYDANTOIN DERIVATIVE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; BINDING SITE; CHEMICAL STRUCTURE; HYDROGEN BOND; IN VITRO STUDY; IN VIVO STUDY; LIGHT EXPOSURE; MOLECULAR MODEL; NONHUMAN; PROTEIN AGGREGATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; STRUCTURE ACTIVITY RELATION;

ALZHEIMER DISEASE; ANIMALS; CLINICAL TRIALS AS TOPIC; HUMANS; HYDROGEN BONDING; MODELS, MOLECULAR; PROTEIN BINDING; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP; TAU PROTEINS;

EID: 84879040199     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm3017317     Document Type: Review

References (215)

1. 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)
2. Braak, H.; Braak, E. Neuropathological stageing of Alzheimer-related changes Acta Neuropathol. 1991, 82, 239-259
3. Rapoport, M.; Dawson, H. N.; Binder, L. I.; Vitek, M. P.; Ferreira, A. Tau is essential to beta-amyloid-induced neurotoxicity Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 6364-6369
4. Roberson, E. D.; Scearce-Levie, K.; Palop, J. J.; Yan, F.; Cheng, I. H.; Wu, T.; Gerstein, H.; Yu, G. Q.; Mucke, L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model Science 2007, 316, 750-754 (Pubitemid 46717684)
5. Hutton, M.; Lewis, J.; Dickson, D.; Yen, S. H.; McGowan, E. Analysis of tauopathies with transgenic mice Trends Mol. Med. 2001, 7, 467-470 (Pubitemid 32964162)
6. Crespo-Biel, N.; Theunis, C.; Van Leuven, F. Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease Int. J. Alzheimer's Dis. 2012, 251426
7. Eisenberg, D.; Jucker, M. The amyloid state of proteins in human diseases Cell 2012, 148, 1188-1203
8. Kolarova, M.; Garcia-Sierra, F.; Bartos, A.; Ricny, J.; Ripova, D. Structure and pathology of tau protein in Alzheimer disease Int. J. Alzheimer's Dis. 2012, 731526
9. Ittner, L. M.; Gotz, J. Amyloid-beta and tau-a toxic pas de deux in Alzheimer's disease Nat. Rev. Neurosci. 2011, 12, 65-72
10. Zempel, H.; Thies, E.; Mandelkow, E.; Mandelkow, E. M. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines J. Neurosci. 2010, 30, 11938-11950
11. Braak, H.; Del Tredici, K. The pathological process underlying Alzheimer's disease in individuals under thirty Acta Neuropathol. 2011, 121, 171-181
12. Lasagna-Reeves, C. A.; Castillo-Carranza, D. L.; Guerrero-Muoz, M. J.; Jackson, G. R.; Kayed, R. Preparation and characterization of neurotoxic tau oligomers Biochemistry 2010, 49, 10039-10041
13. Lasagna-Reeves, C. A.; Castillo-Carranza, D. L.; Sengupta, U.; Sarmiento, J.; Troncoso, J.; Jackson, G. R.; Kayed, R. Identification of oligomers at early stages of tau aggregation in Alzheimer's disease FASEB J. 2012, 26, 1946-1959
14. Patterson, K. R.; Remmers, C.; Fu, Y.; Brooker, S.; Kanaan, N. M.; Vana, L.; Ward, S.; Reyes, J. F.; Philibert, K.; Glucksman, M. J.; Binder, L. I. Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer disease J. Biol. Chem. 2011, 286, 23063-23076
15. Green, R. C.; Schneider, L. S.; Amato, D. A.; Beelen, A. P.; Wilcock, G.; Swabb, E. A.; Zavitz, K. H. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial JAMA, J. Am. Med. Assoc. 2009, 302, 2557-2564
16. Sabbagh, M. N. Drug development for Alzheimer's disease: Where are we now and where are we headed? Am. J. Geriatr. Pharmacother. 2009, 7, 167-185
17. Golde, T. E.; Petrucelli, L.; Lewis, J. Targeting Abeta and tau in Alzheimer's disease, an early interim report Exp. Neurol. 2010, 223, 252-266
18. Hamley, I. W. The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization Chem. Rev. 2012, 112, 5147-5192
19. Estrada, L. D.; Soto, C. Disrupting beta-amyloid aggregation for Alzheimer disease treatment Curr. Top. Med. Chem. 2007, 7, 115-126 (Pubitemid 46062400)
20. Karran, E.; Mercken, M.; De Strooper, B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics Nat. Rev. Drug Discovery 2011, 10, 698-712
21. Di Carlo, M.; Giacomazza, D.; San Biagio, P. L. Alzheimer's disease: biological aspects, therapeutic perspectives and diagnostic tools J. Phys.: Condens. Matter 2012, 24, 244102
22. Mangialasche, F.; Solomon, A.; Winblad, B.; Mecocci, P.; Kivipelto, M. Alzheimer's disease: clinical trials and drug development Lancet Neurol. 2010, 9, 702-716
23. Wischik, C. M.; Rickard, J. E.; Harrington, C. R.; Horsley, D.; Storey, J. M. D.; Marshall, C.; Sinclair, J. P. Preparation of Phenothiazine Derivatives for Treatment of Tauopathy. PCT Int. Appl. WO 2007110630, 2007.
24. Nie, Q.; Du, X. G.; Geng, M. Y. Small molecule inhibitors of amyloid beta peptide aggregation as a potential therapeutic strategy for Alzheimer's disease Acta Pharmacol. Sin. 2011, 32, 545-551
25. Holmes, C.; Boche, D.; Wilkinson, D.; Yadegarfar, G.; Hopkins, V.; Bayer, A.; Jones, R. W.; Bullock, R.; Love, S.; Neal, J. W.; Zotova, E.; Nicoll, J. A. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial Lancet 2008, 372, 216-223 (Pubitemid 351978111)
26. Aisen, P. S.; Vellas, B. Editorial: passive immunotherapy for Alzheimer's disease: What have we learned, and where are we headed? J. Nutr., Health Aging 2013, 17, 49-50
27. Mandelkow, E. M.; Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration Cold Spring Harbor Perspect. Med. 2012, 2, a006247
28. Himmelstein, D. S.; Ward, S. M.; Lancia, J. K.; Patterson, K. R.; Binder, L. I. Tau as a therapeutic target in neurodegenerative disease Pharmacol. Ther. 2012, 136, 8-22
29. Noble, W.; Pooler, A. M.; Hanger, D. P. Advances in tau-based drug discovery Expert Opin. Drug Discovery 2011, 6, 797-810
30. Ballatore, C.; Brunden, K. R.; Trojanowski, J. Q.; Lee, V. M.; Smith, A. B., 3rd; Huryn, D. M. Modulation of protein-protein interactions as a therapeutic strategy for the treatment of neurodegenerative tauopathies Curr. Top. Med. Chem. 2011, 11, 317-330
31. Brunden, K. R.; Trojanowski, J. Q.; Lee, V. M. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies Nat. Rev. Drug Discovery 2009, 8, 783-793
32. Rosenmann, H.; Grigoriadis, N.; Karussis, D.; Boimel, M.; Touloumi, O.; Ovadia, H.; Abramsky, O. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein Arch. Neurol. 2006, 63, 1459-1467 (Pubitemid 44547559)
33. Boimel, M.; Grigoriadis, N.; Lourbopoulos, A.; Haber, E.; Abramsky, O.; Rosenmann, H. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice Exp. Neurol. 2010, 224, 472-485
34. Asuni, A. A.; Boutajangout, A.; Quartermain, D.; Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements J. Neurosci. 2007, 27, 9115-9129 (Pubitemid 47312068)
35. Boutajangout, A.; Quartermain, D.; Sigurdsson, E. M. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model J. Neurosci. 2010, 30, 16559-16566
36. Troquier, L.; Caillierez, R.; Burnouf, S.; Fernandez-Gomez, F. J.; Grosjean, M. E.; Zommer, N.; Sergeant, N.; Schraen-Maschke, S.; Blum, D.; Buee, L. Targeting phospho-Ser422 by active Tau immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach Curr. Alzheimer Res. 2012, 9, 397-405
37. Boutajangout, A.; Ingadottir, J.; Davies, P.; Sigurdsson, E. M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain J. Neurochem. 2011, 118, 658-667
38. Chai, X.; Wu, S.; Murray, T. K.; Kinley, R.; Cella, C. V.; Sims, H.; Buckner, N.; Hanmer, J.; Davies, P.; O'Neill, M. J.; Hutton, M. L.; Citron, M. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression J. Biol. Chem. 2011, 286, 34457-34467
39. Krishnamurthy, P. K.; Deng, Y.; Sigurdsson, E. M. Mechanistic studies of antibody-mediated clearance of Tau aggregates using an ex vivo brain slice model Front. Psychiatry 2011, 2, 59
40. Martin, L.; Latypova, X.; Terro, F. Post-translational modifications of tau protein: implications for Alzheimer's disease Neurochem. Int. 2011, 58, 458-471
41. Hanger, D. P.; Anderton, B. H.; Noble, W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease Trends Mol. Med. 2009, 15, 112-119
42. Min, S. W.; Cho, S. H.; Zhou, Y.; Schroeder, S.; Haroutunian, V.; Seeley, W. W.; Huang, E. J.; Shen, Y.; Masliah, E.; Mukherjee, C.; Meyers, D.; Cole, P. A.; Ott, M.; Gan, L. Acetylation of tau inhibits its degradation and contributes to tauopathy Neuron 2010, 67, 953-966
43. Jana, N. R. Protein homeostasis and aging: role of ubiquitin protein ligases Neurochem. Int. 2012, 60, 443-447
44. Wang, Y.; Martinez-Vicente, M.; Kruger, U.; Kaushik, S.; Wong, E.; Mandelkow, E. M.; Cuervo, A. M.; Mandelkow, E. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing Hum. Mol. Genet. 2009, 18, 4153-4170
45. Ravikumar, B.; Rubinsztein, D. C. Can autophagy protect against neurodegeneration caused by aggregate-prone proteins? NeuroReport 2004, 15, 2443-2445 (Pubitemid 39579328)
46. Kruger, U.; Wang, Y.; Kumar, S.; Mandelkow, E. M. Autophagic degradation of tau in primary neurons and its enhancement by trehalose Neurobiol. Aging 2012, 33, 2291-2305
47. Luo, W.; Dou, F.; Rodina, A.; Chip, S.; Kim, J.; Zhao, Q.; Moulick, K.; Aguirre, J.; Wu, N.; Greengard, P.; Chiosis, G. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 9511-9516 (Pubitemid 47185810)
48. Dickey, C. A.; Kamal, A.; Lundgren, K.; Klosak, N.; Bailey, R. M.; Dunmore, J.; Ash, P.; Shoraka, S.; Zlatkovic, J.; Eckman, C. B.; Patterson, C.; Dickson, D. W.; Nahman, N. S., Jr.; Hutton, M.; Burrows, F.; Petrucelli, L. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins J. Clin. Invest. 2007, 117, 648-658 (Pubitemid 46348523)
49. Dickey, C. A.; Dunmore, J.; Lu, B.; Wang, J. W.; Lee, W. C.; Kamal, A.; Burrows, F.; Eckman, C.; Hutton, M.; Petrucelli, L. HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites FASEB J. 2006, 20, 753-755 (Pubitemid 46671204)
50. Salminen, A.; Ojala, J.; Kaarniranta, K.; Hiltunen, M.; Soininen, H. Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer's disease Prog. Neurobiol. 2011, 93, 99-110
51. Shimura, H.; Schwartz, D.; Gygi, S. P.; Kosik, K. S. CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival J. Biol. Chem. 2004, 279, 4869-4876 (Pubitemid 38199082)
52. Jeganathan, S.; von Bergen, M.; Mandelkow, E. M.; Mandelkow, E. The natively unfolded character of tau and its aggregation to Alzheimer-like paired helical filaments Biochemistry 2008, 47, 10526-10539
53. Schweers, O.; Schonbrunn-Hanebeck, E.; Marx, A.; Mandelkow, E. Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure J. Biol. Chem. 1994, 269, 24290-24297
54. Jeganathan, S.; Hascher, A.; Chinnathambi, S.; Biernat, J.; Mandelkow, E. M.; Mandelkow, E. Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC-1) conformation J. Biol. Chem. 2008, 283, 32066-32076
55. Mukrasch, M. D.; Bibow, S.; Korukottu, J.; Jeganathan, S.; Biernat, J.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M. Structural polymorphism of 441-residue tau at single residue resolution PLoS Biol. 2009, 7, e34
56. Mukrasch, M. D.; von Bergen, M.; Biernat, J.; Fischer, D.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M. The "jaws" of the tau-microtubule interaction J. Biol. Chem. 2007, 282, 12230-12239
57. von Bergen, M.; Friedhoff, P.; Biernat, J.; Heberle, J.; Mandelkow, E. M.; Mandelkow, E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5129-5134 (Pubitemid 30313683)
58. Daebel, V.; Chinnathambi, S.; Biernat, J.; Schwalbe, M.; Habenstein, B.; Loquet, A.; Akoury, E.; Tepper, K.; Muller, H.; Baldus, M.; Griesinger, C.; Zweckstetter, M.; Mandelkow, E.; Vijayan, V.; Lange, A. beta-Sheet core of tau paired helical filaments revealed by solid-state NMR J. Am. Chem. Soc. 2012, 134, 13982-13989
59. Delacourte, A. Tauopathies: recent insights into old diseases Folia Neuropathol. 2005, 43, 244-257 (Pubitemid 43109283)
60. Kidd, M. Paired helical filaments in electron microscopy of Alzheimer's disease Nature 1963, 197, 192-193
61. Wegmann, S.; Jung, Y. J.; Chinnathambi, S.; Mandelkow, E. M.; Mandelkow, E.; Muller, D. J. Human Tau isoforms assemble into ribbon-like fibrils that display polymorphic structure and stability J. Biol. Chem. 2010, 285, 27302-27313
62. Margittai, M.; Langen, R. Template-assisted filament growth by parallel stacking of tau Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 10278-10283 (Pubitemid 38924916)
63. von Bergen, M.; Barghorn, S.; Biernat, J.; Mandelkow, E. M.; Mandelkow, E. Tau aggregation is driven by a transition from random coil to beta sheet structure Biochim. Biophys. Acta 2005, 1739, 158-166 (Pubitemid 40018535)
64. Heiser, V.; Engemann, S.; Brocker, W.; Dunkel, I.; Boeddrich, A.; Waelter, S.; Nordhoff, E.; Lurz, R.; Schugardt, N.; Rautenberg, S.; Herhaus, C.; Barnickel, G.; Bottcher, H.; Lehrach, H.; Wanker, E. E. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay Proc. Natl. Acad. Sci. U.S.A. 2002, 99 (Suppl. 4) 16400-16406 (Pubitemid 35470985)
65. Taniguchi, S.; Suzuki, N.; Masuda, M.; Hisanaga, S.; Iwatsubo, T.; Goedert, M.; Hasegawa, M. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins J. Biol. Chem. 2005, 280, 7614-7623 (Pubitemid 40349654)
66. 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, 27-37 (Pubitemid 43881385)
67. Reinke, A. A.; Gestwicki, J. E. Insight into amyloid structure using chemical probes Chem. Biol. Drug Des. 2011, 77, 399-411
68. Kelly, J. W. Alternative conformations of amyloidogenic proteins govern their behavior Curr. Opin. Struct. Biol. 1996, 6, 11-17 (Pubitemid 26073939)
69. von Bergen, M.; Barghorn, S.; Li, L.; Marx, A.; Biernat, J.; Mandelkow, E. M.; Mandelkow, E. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure J. Biol. Chem. 2001, 276, 48165-48174
70. Lewis, J.; McGowan, E.; Rockwood, J.; Melrose, H.; Nacharaju, P.; Van Slegtenhorst, M.; Gwinn-Hardy, K.; Paul Murphy, M.; Baker, M.; Yu, X.; Duff, K.; Hardy, J.; Corral, A.; Lin, W. L.; Yen, S. H.; Dickson, D. W.; Davies, P.; Hutton, M. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein Nat. Genet. 2000, 25, 402-405 (Pubitemid 32983430)
71. Khlistunova, I.; Biernat, J.; Wang, Y.; Pickhardt, M.; von Bergen, M.; Gazova, Z.; Mandelkow, E.; Mandelkow, E. M. Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs J. Biol. Chem. 2006, 281, 1205-1214
72. Pickhardt, M.; von Bergen, M.; Gazova, Z.; Hascher, A.; Biernat, J.; Mandelkow, E. M.; Mandelkow, E. Screening for inhibitors of tau polymerization Curr. Alzheimer Res. 2005, 2, 219-226 (Pubitemid 40862884)
73. Morelli, X.; Bourgeas, R.; Roche, P. Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I) Curr. Opin. Chem. Biol. 2011, 15, 475-481
74. Sawaya, M. R.; Sambashivan, S.; Nelson, R.; Ivanova, M. I.; Sievers, S. A.; Apostol, M. I.; Thompson, M. J.; Balbirnie, M.; Wiltzius, J. J.; McFarlane, H. T.; Madsen, A. O.; Riekel, C.; Eisenberg, D. Atomic structures of amyloid cross-beta spines reveal varied steric zippers Nature 2007, 447, 453-457 (Pubitemid 46816731)
75. Peterson, D. W.; Zhou, H.; Dahlquist, F. W.; Lew, J. A soluble oligomer of tau associated with fiber formation analyzed by NMR Biochemistry 2008, 47, 7393-7404 (Pubitemid 351991018)
76. Barghorn, S.; Mandelkow, E. Toward a unified scheme for the aggregation of tau into Alzheimer paired helical filaments Biochemistry 2002, 41, 14885-14896 (Pubitemid 35470667)
77. Schweers, O.; Mandelkow, E. M.; Biernat, J.; Mandelkow, E. Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 8463-8467
78. Laganowsky, A.; Liu, C.; Sawaya, M. R.; Whitelegge, J. P.; Park, J.; Zhao, M.; Pensalfini, A.; Soriaga, A. B.; Landau, M.; Teng, P. K.; Cascio, D.; Glabe, C.; Eisenberg, D. Atomic view of a toxic amyloid small oligomer Science 2012, 335, 1228-1231
79. Walsh, D. M.; Selkoe, D. J. A beta oligomers-a decade of discovery J. Neurochem. 2007, 101, 1172-1184
80. Podlisny, M. B.; Ostaszewski, B. L.; Squazzo, S. L.; Koo, E. H.; Rydell, R. E.; Teplow, D. B.; Selkoe, D. J. Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture J. Biol. Chem. 1995, 270, 9564-9570
81. Campioni, S.; Mannini, B.; Zampagni, M.; Pensalfini, A.; Parrini, C.; Evangelisti, E.; Relini, A.; Stefani, M.; Dobson, C. M.; Cecchi, C.; Chiti, F. A causative link between the structure of aberrant protein oligomers and their toxicity Nat. Chem. Biol. 2010, 6, 140-147
82. Braun, N.; Zacharias, M.; Peschek, J.; Kastenmuller, A.; Zou, J.; Hanzlik, M.; Haslbeck, M.; Rappsilber, J.; Buchner, J.; Weinkauf, S. Multiple molecular architectures of the eye lens chaperone alphaB-crystallin elucidated by a triple hybrid approach Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 20491-20496
83. Shafrir, Y.; Durell, S. R.; Anishkin, A.; Guy, H. R. Beta-barrel models of soluble amyloid beta oligomers and annular protofibrils Proteins 2010, 78, 3458-3472
84. Cheng, P. N.; Liu, C.; Zhao, M.; Eisenberg, D.; Nowick, J. S. Amyloid beta-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity Nat. Chem. 2012, 4, 927-933
85. Landau, M.; Sawaya, M. R.; Faull, K. F.; Laganowsky, A.; Jiang, L.; Sievers, S. A.; Liu, J.; Barrio, J. R.; Eisenberg, D. Towards a pharmacophore for amyloid PLoS Biol. 2011, 9, e1001080
86. Sievers, S. A.; Karanicolas, J.; Chang, H. W.; Zhao, A.; Jiang, L.; Zirafi, O.; Stevens, J. T.; Munch, J.; Baker, D.; Eisenberg, D. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation Nature 2011, 475, 96-100
87. Zheng, J.; Liu, C.; Sawaya, M. R.; Vadla, B.; Khan, S.; Woods, R. J.; Eisenberg, D.; Goux, W. J.; Nowick, J. S. Macrocyclic beta-sheet peptides that inhibit the aggregation of a tau-protein-derived hexapeptide J. Am. Chem. Soc. 2011, 133, 3144-3157
88. Wischik, C. M.; Edwards, P. C.; Lai, R. Y.; Roth, M.; Harrington, C. R. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 11213-11218 (Pubitemid 26333144)
89. Wainwright, M.; Amaral, L. The phenothiazinium chromophore and the evolution of antimalarial drugs Trop. Med. Int. Health 2005, 10, 501-511 (Pubitemid 40806655)
90. Schirmer, R. H.; Adler, H.; Pickhardt, M.; Mandelkow, E. Lest we forget you-methylene blue.. Neurobiol Aging 2011, 32, 2325 e2327-e2316
91. Josefsen, L. B.; Boyle, R. W. Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics Theranostics 2012, 2, 916-966
92. Bruchey, A. K.; Gonzalez-Lima, F. Behavioral, physiological and biochemical hormetic responses to the autoxidizable dye methylene blue Am. J. Pharmacol. Toxicol. 2008, 3, 72-79
93. Ohlow, M. J.; Moosmann, B. Phenothiazine: the seven lives of pharmacology's first lead structure Drug Discovery Today 2011, 16, 119-131
94. DiSanto, A. R.; Wagner, J. G. Pharmacokinetics of highly ionized drugs. II. Methylene blue-absorption, metabolism, and excretion in man and dog after oral administration J. Pharm. Sci. 1972, 61, 1086-1090
95. Walter-Sack, I.; Rengelshausen, J.; Oberwittler, H.; Burhenne, J.; Mueller, O.; Meissner, P.; Mikus, G. High absolute bioavailability of methylene blue given as an aqueous oral formulation Eur. J. Clin. Pharmacol. 2009, 65, 179-189
96. Peter, C.; Hongwan, D.; Kupfer, A.; Lauterburg, B. H. Pharmacokinetics and organ distribution of intravenous and oral methylene blue Eur. J. Clin. Pharmacol. 2000, 56, 247-250 (Pubitemid 30456685)
97. Meijer, D. K.; Weert, B.; Vermeer, G. A. Pharmacokinetics of biliary excretion in man. VI. Indocyanine green Eur. J. Clin. Pharmacol. 1988, 35, 295-303
98. Medina, D. X.; Caccamo, A.; Oddo, S. Methylene blue reduces abeta levels and rescues early cognitive deficit by increasing proteasome activity Brain Pathol. 2011, 21, 140-149
99. van Bebber, F.; Paquet, D.; Hruscha, A.; Schmid, B.; Haass, C. Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish Neurobiol. Dis. 2010, 39, 265-271
100. Congdon, E. E.; Wu, J. W.; Myeku, N.; Figueroa, Y. H.; Herman, M.; Marinec, P. S.; Gestwicki, J. E.; Dickey, C. A.; Yu, W. H.; Duff, K. E. Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo Autophagy 2012, 8, 609-622
101. Buchholz, K.; Comini, M. A.; Wissenbach, D.; Schirmer, R. H.; Krauth-Siegel, R. L.; Gromer, S. Cytotoxic interactions of methylene blue with trypanosomatid-specific disulfide reductases and their dithiol products Mol. Biochem. Parasitol. 2008, 160, 65-69 (Pubitemid 351694358)
102. Atamna, H.; Nguyen, A.; Schultz, C.; Boyle, K.; Newberry, J.; Kato, H.; Ames, B. N. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways FASEB J. 2008, 22, 703-712 (Pubitemid 351348123)
103. Crowe, A.; Ballatore, C.; Hyde, E.; Trojanowski, J. Q.; Lee, V. M. High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation Biochem. Biophys. Res. Commun. 2007, 358, 1-6 (Pubitemid 46719073)
104. Buchholz, K.; Schirmer, R. H.; Eubel, J. K.; Akoachere, M. B.; Dandekar, T.; Becker, K.; Gromer, S. Interactions of methylene blue with human disulfide reductases and their orthologues from Plasmodium falciparum Antimicrob. Agents Chemother. 2008, 52, 183-191
105. Aisen, P. S.; Gauthier, S.; Vellas, B.; Briand, R.; Saumier, D.; Laurin, J.; Garceau, D. Alzhemed: a potential treatment for Alzheimer's disease Curr. Alzheimer Res. 2007, 4, 473-478 (Pubitemid 47416642)
106. Gervais, F.; Paquette, J.; Morissette, C.; Krzywkowski, P.; Yu, M.; Azzi, M.; Lacombe, D.; Kong, X.; Aman, A.; Laurin, J.; Szarek, W. A.; Tremblay, P. Targeting soluble Abeta peptide with tramiprosate for the treatment of brain amyloidosis Neurobiol. Aging 2007, 28, 537-547 (Pubitemid 46282205)
107. Salloway, S.; Sperling, R.; Keren, R.; Porsteinsson, A. P.; van Dyck, C. H.; Tariot, P. N.; Gilman, S.; Arnold, D.; Abushakra, S.; Hernandez, C.; Crans, G.; Liang, E.; Quinn, G.; Bairu, M.; Pastrak, A.; Cedarbaum, J. M.; Investigators, E. A. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease Neurology 2011, 77, 1253-1262
108. McLaurin, J.; Kierstead, M. E.; Brown, M. E.; Hawkes, C. A.; Lambermon, M. H.; Phinney, A. L.; Darabie, A. A.; Cousins, J. E.; French, J. E.; Lan, M. F.; Chen, F.; Wong, S. S.; Mount, H. T.; Fraser, P. E.; Westaway, D.; St George-Hyslop, P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model Nat. Med. 2006, 12, 801-808 (Pubitemid 44050070)
109. McLaurin, J.; Golomb, R.; Jurewicz, A.; Antel, J. P.; Fraser, P. E. Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -induced toxicity J. Biol. Chem. 2000, 275, 18495-18502 (Pubitemid 30414810)
110. Rezai-Zadeh, K.; Shytle, D.; Sun, N.; Mori, T.; Hou, H.; Jeanniton, D.; Ehrhart, J.; Townsend, K.; Zeng, J.; Morgan, D.; Hardy, J.; Town, T.; Tan, J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice J. Neurosci. 2005, 25, 8807-8814 (Pubitemid 41362059)
111. Ehrnhoefer, D. E.; Bieschke, J.; Boeddrich, A.; Herbst, M.; Masino, L.; Lurz, R.; Engemann, S.; Pastore, A.; Wanker, E. E. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers Nat. Struct. Mol. Biol. 2008, 15, 558-566 (Pubitemid 351799141)
112. Bieschke, J.; Russ, J.; Friedrich, R. P.; Ehrnhoefer, D. E.; Wobst, H.; Neugebauer, K.; Wanker, E. E. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 7710-7715
113. Bieschke, J.; Herbst, M.; Wiglenda, T.; Friedrich, R. P.; Boeddrich, A.; Schiele, F.; Kleckers, D.; Lopez del Amo, J. M.; Gruning, B. A.; Wang, Q.; Schmidt, M. R.; Lurz, R.; Anwyl, R.; Schnoegl, S.; Fandrich, M.; Frank, R. F.; Reif, B.; Gunther, S.; Walsh, D. M.; Wanker, E. E. Small-molecule conversion of toxic oligomers to nontoxic beta-sheet-rich amyloid fibrils Nat. Chem. Biol. 2012, 8, 93-101
114. Bush, A. I. The metallobiology of Alzheimer's disease Trends Neurosci. 2003, 26, 207-214 (Pubitemid 36412003)
115. Jenagaratnam, L.; McShane, R. Clioquinol for the treatment of Alzheimer's disease Cochrane Database Syst. Rev. 2006, CD005380
116. Sampson, E.; Jenagaratnam, L.; McShane, R. Metal protein attenuating compounds for the treatment of Alzheimer's disease Cochrane Database Syst. Rev. 2008, CD005380
117. Lei, P.; Ayton, S.; Finkelstein, D. I.; Spoerri, L.; Ciccotosto, G. D.; Wright, D. K.; Wong, B. X.; Adlard, P. A.; Cherny, R. A.; Lam, L. Q.; Roberts, B. R.; Volitakis, I.; Egan, G. F.; McLean, C. A.; Cappai, R.; Duce, J. A.; Bush, A. I. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export Nat. Med. 2012, 18, 291-295
118. Lecanu, L.; Yao, W.; Teper, G. L.; Yao, Z. X.; Greeson, J.; Papadopoulos, V. Identification of naturally occurring spirostenols preventing beta-amyloid-induced neurotoxicity Steroids 2004, 69, 1-16 (Pubitemid 38050297)
119. Papadopoulos, V.; Lecanu, L. Caprospinol: discovery of a steroid drug candidate to treat Alzheimer's disease based on 22 R -hydroxycholesterol structure and properties J. Neuroendocrinol. 2012, 24, 93-101
120. Nakagami, Y.; Nishimura, S.; Murasugi, T.; Kaneko, I.; Meguro, M.; Marumoto, S.; Kogen, H.; Koyama, K.; Oda, T. 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, 676-682 (Pubitemid 35333093)
121. Walsh, D. M.; Townsend, M.; Podlisny, M. B.; Shankar, G. M.; Fadeeva, J. V.; El Agnaf, O.; Hartley, D. M.; Selkoe, D. J. Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation J. Neurosci. 2005, 25, 2455-2462 (Pubitemid 40365155)
122. Scopes, D. I.; O'Hare, E.; Jeggo, R.; Whyment, A. D.; Spanswick, D.; Kim, E. M.; Gannon, J.; Amijee, H.; Treherne, J. M. Abeta oligomer toxicity inhibitor protects memory in models of synaptic toxicity Br. J. Pharmacol. 2012, 167, 383-392
123. Congdon, E. E.; Necula, M.; Blackstone, R. D.; Kuret, J. Potency of a tau fibrillization inhibitor is influenced by its aggregation state Arch. Biochem. Biophys. 2007, 465, 127-135 (Pubitemid 47283987)
124. Crowe, A.; Huang, W.; Ballatore, C.; Johnson, R. L.; Hogan, A. M.; Huang, R.; Wichterman, J.; McCoy, J.; Huryn, D.; Auld, D. S.; Smith, A. B., 3rd; Inglese, J.; Trojanowski, J. Q.; Austin, C. P.; Brunden, K. R.; Lee, V. M. Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening Biochemistry 2009, 48, 7732-7745
125. Friedhoff, P.; Schneider, A.; Mandelkow, E. M.; Mandelkow, E. Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution Biochemistry 1998, 37, 10223-10230 (Pubitemid 28366378)
126. Zhang, J. H.; Chung, T. D.; Oldenburg, K. R. A simple statistical parameter for use in evaluation and validation of high throughput screening assays J. Biomol. Screening 1999, 4, 67-73 (Pubitemid 29278954)
127. Barghorn, S.; Davies, P.; Mandelkow, E. Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro are based on beta-structure in the core domain Biochemistry 2004, 43, 1694-1703 (Pubitemid 38200576)
128. Schneider, A.; Biernat, J.; von Bergen, M.; Mandelkow, E.; Mandelkow, E. M. Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments Biochemistry 1999, 38, 3549-3558
129. Bulic, B.; Pickhardt, M.; Khlistunova, I.; Biernat, J.; Mandelkow, E. M.; Mandelkow, E.; Waldmann, H. Rhodanine-based tau aggregation inhibitors in cell models of tauopathy Angew. Chem., Int. Ed. 2007, 46, 9215-9219 (Pubitemid 350292144)
130. Larbig, G.; Pickhardt, M.; Lloyd, D. G.; Schmidt, B.; Mandelkow, E. Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: a ligand based approach results in successful scaffold hopping Curr. Alzheimer Res. 2007, 4, 315-323 (Pubitemid 47025430)
131. Pickhardt, M.; Biernat, J.; Khlistunova, I.; Wang, Y. P.; Gazova, Z.; Mandelkow, E. M.; Mandelkow, E. N -Phenylamine derivatives as aggregation inhibitors in cell models of tauopathy Curr. Alzheimer Res. 2007, 4, 397-402 (Pubitemid 47416632)
132. Khlistunova, I.; Pickhardt, M.; Biernat, J.; Wang, Y.; Mandelkow, E. M.; Mandelkow, E. Inhibition of tau aggregation in cell models of tauopathy Curr. Alzheimer Res. 2007, 4, 544-546 (Pubitemid 350248387)
133. Fatouros, C.; Pir, G. J.; Biernat, J.; Koushika, S. P.; Mandelkow, E.; Mandelkow, E. M.; Schmidt, E.; Baumeister, R. Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity Hum. Mol. Genet. 2012, 21, 3587-3603
134. Messing, L.; Decker, J. M.; Joseph, M.; Mandelkow, E.; Mandelkow, E. M. Cascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors Neurobiol. Aging 2013, 34, 1343-1354
135. Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouysegu, L. Plant polyphenols: chemical properties, biological activities, and synthesis Angew. Chem., Int. Ed. 2011, 50, 586-621
136. Meng, X.; Munishkina, L. A.; Fink, A. L.; Uversky, V. N. Effects of various flavonoids on the alpha-synuclein fibrillation process Parkinson's Dis. 2010, 2010, 650794
137. Berhanu, W. M.; Masunov, A. E. Natural polyphenols as inhibitors of amyloid aggregation. Molecular dynamics study of GNNQQNY heptapeptide decamer Biophys. Chem. 2010, 149, 12-21
138. Bolander, A.; Kieser, D.; Voss, C.; Bauer, S.; Schon, C.; Burgold, S.; Bittner, T.; Holzer, J.; Heyny-von Haussen, R.; Mall, G.; Goetschy, V.; Czech, C.; Knust, H.; Berger, R.; Herms, J.; Hilger, I.; Schmidt, B. Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines as imaging agents for Tau fibrils and beta-amyloid plaques in Alzheimer's disease models J. Med. Chem. 2012, 55, 9170-9180
139. Howlett, D. R.; George, A. R.; Owen, D. E.; Ward, R. V.; Markwell, R. E. Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer beta-amyloid fibril formation Biochem. J. 1999, 343 (Part 2) 419-423 (Pubitemid 29511777)
140. Yang, F.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S. S.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. M. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo J. Biol. Chem. 2005, 280, 5892-5901 (Pubitemid 40280072)
141. Pickhardt, M.; Gazova, Z.; von Bergen, M.; Khlistunova, I.; Wang, Y.; Hascher, A.; Mandelkow, E. M.; Biernat, J.; Mandelkow, E. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells J. Biol. Chem. 2005, 280, 3628-3635 (Pubitemid 40223830)
142. Ho, L.; Yemul, S.; Wang, J.; Pasinetti, G. M. Grape seed polyphenolic extract as a potential novel therapeutic agent in tauopathies J. Alzheimer's Dis. 2009, 16, 433-439
143. Ksiezak-Reding, H.; Ho, L.; Santa-Maria, I.; Diaz-Ruiz, C.; Wang, J.; Pasinetti, G. M. Ultrastructural alterations of Alzheimer's disease paired helical filaments by grape seed-derived polyphenols Neurobiol. Aging 2012, 33, 1427-1439
144. Ferruzzi, M. G.; Lobo, J. K.; Janle, E. M.; Cooper, B.; Simon, J. E.; Wu, Q. L.; Welch, C.; Ho, L.; Weaver, C.; Pasinetti, G. M. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease J. Alzheimer's Dis. 2009, 18, 113-124
145. Lopez Del Amo, J. M.; Fink, U.; Dasari, M.; Grelle, G.; Wanker, E. E.; Bieschke, J.; Reif, B. Structural properties of EGCG-induced, nontoxic Alzheimer's disease Abeta oligomers J. Mol. Biol. 2012, 421, 517-524
146. Hu, M. Commentary: bioavailability of flavonoids and polyphenols: call to arms Mol. Pharmaceutics 2007, 4, 803-806
147. Mereles, D.; Hunstein, W. Epigallocatechin-3-gallate (EGCG) for clinical trials: more pitfalls than promises? Int. J. Mol. Sci. 2011, 12, 5592-5603
148. Wasan, K. M.; Brocks, D. R.; Lee, S. D.; Sachs-Barrable, K.; Thornton, S. J. Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery Nat. Rev. Drug Discovery 2008, 7, 84-99
149. Ertl, P.; Roggo, S.; Schuffenhauer, A. Natural product-likeness score and its application for prioritization of compound libraries J. Chem. Inf. Model. 2008, 48, 68-74 (Pubitemid 351271051)
150. Ganesan, A. The impact of natural products upon modern drug discovery Curr. Opin. Chem. Biol. 2008, 12, 306-317
151. Teng, Z. H.; Zhou, S. Y.; Yang, R. T.; Liu, X. Y.; Liu, R. W.; Yang, X.; Zhang, B. L.; Yang, J. Y.; Cao, D. Y.; Mei, Q. B. Quantitation assay for absorption and first-pass metabolism of emodin in isolated rat small intestine using liquid chromatography-tandem mass spectrometry Biol. Pharm. Bull. 2007, 30, 1628-1633 (Pubitemid 47403235)
152. Mueller, S. O.; Schmitt, M.; Dekant, W.; Stopper, H.; Schlatter, J.; Schreier, P.; Lutz, W. K. Occurrence of emodin, chrysophanol and physcion in vegetables, herbs and liquors. Genotoxicity and anti-genotoxicity of the anthraquinones and of the whole plants Food Chem. Toxicol. 1999, 37, 481-491 (Pubitemid 29306913)
153. Xu, X.; Persson, H. L.; Richardson, D. R. Molecular pharmacology of the interaction of anthracyclines with iron Mol. Pharmacol. 2005, 68, 261-271 (Pubitemid 41058288)
154. Patani, G. A.; LaVoie, E. J. Bioisosterism: a rational approach in drug design Chem. Rev. 1996, 96, 3147-3176 (Pubitemid 126641132)
155. Waters, M. L. Aromatic interactions in model systems Curr. Opin. Chem. Biol. 2002, 6, 736-741 (Pubitemid 35449331)
156. Ahn, J. H.; Kim, S. J.; Park, W. S.; Cho, S. Y.; Ha, J. D.; Kim, S. S.; Kang, S. K.; Jeong, D. G.; Jung, S. K.; Lee, S. H.; Kim, H. M.; Park, S. K.; Lee, K. H.; Lee, C. W.; Ryu, S. E.; Choi, J. K. Synthesis and biological evaluation of rhodanine derivatives as PRL-3 inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 2996-2999
157. Cutshall, N. S.; O'Day, C.; Prezhdo, M. Rhodanine derivatives as inhibitors of JSP-1 Bioorg. Med. Chem. Lett. 2005, 15, 3374-3379 (Pubitemid 40835739)
158. Gualtieri, M.; Bastide, L.; Villain-Guillot, P.; Michaux-Charachon, S.; Latouche, J.; Leonetti, J. P. In vitro activity of a new antibacterial rhodanine derivative against Staphylococcus epidermidis biofilms J. Antimicrob. Chemother. 2006, 58, 778-783 (Pubitemid 44390952)
159. Hu, M.; Li, J.; Yao, S. Q. In situ "click" assembly of small molecule matrix metalloprotease inhibitors containing zinc-chelating groups Org. Lett. 2008, 10, 5529-5531
160. Irvine, M. W.; Patrick, G. L.; Kewney, J.; Hastings, S. F.; MacKenzie, S. J. Rhodanine derivatives as novel inhibitors of PDE4 Bioorg. Med. Chem. Lett. 2008, 18, 2032-2037 (Pubitemid 351380882)
161. Johnson, S. L.; Chen, L. H.; Harbach, R.; Sabet, M.; Savinov, A.; Cotton, N. J.; Strongin, A.; Guiney, D.; Pellecchia, M. Rhodanine derivatives as selective protease inhibitors against bacterial toxins Chem. Biol. Drug Des. 2008, 71, 131-139 (Pubitemid 351160982)
162. Kumar, G.; Parasuraman, P.; Sharma, S. K.; Banerjee, T.; Karmodiya, K.; Surolia, N.; Surolia, A. Discovery of a rhodanine class of compounds as inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase J. Med. Chem. 2007, 50, 2665-2675 (Pubitemid 46896074)
163. Martinez, A.; Alonso, M.; Castro, A.; Dorronsoro, I.; Gelpi, J. L.; Luque, F. J.; Perez, C.; Moreno, F. J. SAR and 3D-QSAR studies on thiadiazolidinone derivatives: exploration of structural requirements for glycogen synthase kinase 3 inhibitors J. Med. Chem. 2005, 48, 7103-7112 (Pubitemid 41743624)
164. Russell, A. J.; Westwood, I. M.; Crawford, M. H.; Robinson, J.; Kawamura, A.; Redfield, C.; Laurieri, N.; Lowe, E. D.; Davies, S. G.; Sim, E. Selective small molecule inhibitors of the potential breast cancer marker, human arylamine N -acetyltransferase 1, and its murine homologue, mouse arylamine N -acetyltransferase 2 Bioorg. Med. Chem. 2009, 17, 905-918
165. Villain-Guillot, P.; Gualtieri, M.; Bastide, L.; Roquet, F.; Martinez, J.; Amblard, M.; Pugniere, M.; Leonetti, J. P. Structure-activity relationships of phenyl-furanyl-rhodanines as inhibitors of RNA polymerase with antibacterial activity on biofilms J. Med. Chem. 2007, 50, 4195-4204 (Pubitemid 47301750)
166. Zervosen, A.; Lu, W. P.; Chen, Z.; White, R. E.; Demuth, T. P., Jr.; Frere, J. M. Interactions between penicillin-binding proteins (PBPs) and two novel classes of PBP inhibitors, arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones Antimicrob. Agents Chemother. 2004, 48, 961-969 (Pubitemid 38280350)
167. Carlson, E. E.; May, J. F.; Kiessling, L. L. Chemical probes of UDP-galactopyranose mutase Chem. Biol. 2006, 13, 825-837 (Pubitemid 44247773)
168. Hotta, N.; Akanuma, Y.; Kawamori, R.; Matsuoka, K.; Oka, Y.; Shichiri, M.; Toyota, T.; Nakashima, M.; Yoshimura, I.; Sakamoto, N.; Shigeta, Y. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative aldose reductase inhibitor-diabetes complications trial Diabetes Care 2006, 29, 1538-1544 (Pubitemid 44127578)
169. Sturm, K.; Levstik, L.; Demopoulos, V. J.; Kristl, A. Permeability characteristics of novel aldose reductase inhibitors using rat jejunum in vitro Eur. J. Pharm. Sci. 2006, 28, 128-133
170. Necula, M.; Kayed, R.; Milton, S.; Glabe, C. G. Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct J. Biol. Chem. 2007, 282, 10311-10324 (Pubitemid 47093410)
171. Pickhardt, M.; Larbig, G.; Khlistunova, I.; Coksezen, A.; Meyer, B.; Mandelkow, E. M.; Schmidt, B.; Mandelkow, E. Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tau aggregation and toxicity in vitro and in cells Biochemistry 2007, 46, 10016-10023 (Pubitemid 47378592)
172. Taghavi, A.; Nasir, S.; Pickhardt, M.; Heyny-von Haussen, R.; Mall, G.; Mandelkow, E.; Mandelkow, E. M.; Schmidt, B. N ′-Benzylidene- benzohydrazides as novel and selective tau-PHF ligands J. Alzheimer's Dis. 2011, 27, 835-843
173. Vijaya Raj, K. K.; Narayana, B.; Ashalatha, B. V.; Suchetha Kumari, N.; Sarojini, B. K. Synthesis of some bioactive 2-bromo-5-methoxy- N ′-[4-(aryl)-1,3-thiazol-2-yl]benzohydrazide derivatives Eur. J. Med. Chem. 2007, 42, 425-429 (Pubitemid 46349366)
174. Sonar, V. N.; Crooks, P. A. Synthesis and antitubercular activity of a series of hydrazone and nitrovinyl analogs derived from heterocyclic aldehydes J. Enzyme Inhib. Med. Chem. 2009, 24, 117-124
175. Hafez, H. N.; El-Gazzar, A. B. Design and synthesis of 3-pyrazolyl-thiophene, thieno[2,3- d ]pyrimidines as new bioactive and pharmacological activities Bioorg. Med. Chem. Lett. 2008, 18, 5222-5227
176. Obach, R. S.; Kalgutkar, A. S.; Ryder, T. F.; Walker, G. S. In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam Chem. Res. Toxicol. 2008, 21, 1890-1899
177. Preziosi, P. Isoniazid: metabolic aspects and toxicological correlates Curr. Drug Metab. 2007, 8, 839-851 (Pubitemid 350238914)
178. Timmins, G. S.; Deretic, V. Mechanisms of action of isoniazid Mol. Microbiol. 2006, 62, 1220-1227 (Pubitemid 44707189)
179. Pessayre, D.; de Saint-Louvent, P.; Degott, C.; Bernuau, J.; Rueff, B.; Benhamou, J. P. Iproclozide fulminant hepatitis. Possible role of enzyme induction Gastroenterology 1978, 75, 492-496 (Pubitemid 8388859)
180. Fagervall, I.; Ross, S. B. Inhibition of monoamine oxidase in monoaminergic neurones in the rat brain by irreversible inhibitors Biochem. Pharmacol. 1986, 35, 1381-1387 (Pubitemid 16037049)
181. Park, B. K.; Kitteringham, N. R.; Maggs, J. L.; Pirmohamed, M.; Williams, D. P. The role of metabolic activation in drug-induced hepatotoxicity Annu. Rev. Pharmacol. Toxicol. 2005, 45, 177-202 (Pubitemid 40261802)
182. Koechlin, B. A.; Schwartz, M. A.; Oberhaensli, W. E. Metabolism of C-14-iproniazid and C-14-isocarboxazid in man J. Pharmacol. Exp. Ther. 1962, 138, 11-20
183. Shimada, T.; Mimura, M.; Inoue, K.; Nakamura, S.; Oda, H.; Ohmori, S.; Yamazaki, H. Cytochrome P450-dependent drug oxidation activities in liver microsomes of various animal species including rats, guinea pigs, dogs, monkeys, and humans Arch. Toxicol. 1997, 71, 401-408 (Pubitemid 27214472)
184. Klunk, W. E.; Wang, Y.; Huang, G. F.; Debnath, M. L.; Holt, D. P.; Mathis, C. A. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain Life Sci. 2001, 69, 1471-1484 (Pubitemid 32786721)
185. Necula, M.; Chirita, C. N.; Kuret, J. Cyanine dye N744 inhibits tau fibrillization by blocking filament extension: implications for the treatment of tauopathic neurodegenerative diseases Biochemistry 2005, 44, 10227-10237 (Pubitemid 41076818)
186. Klunk, W. E.; Lopresti, B. J.; Ikonomovic, M. D.; Lefterov, I. M.; Koldamova, R. P.; Abrahamson, E. E.; Debnath, M. L.; Holt, D. P.; Huang, G. F.; Shao, L.; DeKosky, S. T.; Price, J. C.; Mathis, C. A. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain J. Neurosci. 2005, 25, 10598-10606 (Pubitemid 41681907)
187. Mathis, C. A.; Bacskai, B. J.; Kajdasz, S. T.; McLellan, M. E.; Frosch, M. P.; Hyman, B. T.; Holt, D. P.; Wang, Y.; Huang, G. F.; Debnath, M. L.; Klunk, W. E. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain Bioorg. Med. Chem. Lett. 2002, 12, 295-298 (Pubitemid 34113887)
188. Mathis, C. A.; Lopresti, B. J.; Klunk, W. E. Impact of amyloid imaging on drug development in Alzheimer's disease Nucl. Med. Biol. 2007, 34, 809-822 (Pubitemid 47503823)
189. Ikonomovic, M. D.; Klunk, W. E.; Abrahamson, E. E.; Mathis, C. A.; Price, J. C.; Tsopelas, N. D.; Lopresti, B. J.; Ziolko, S.; Bi, W.; Paljug, W. R.; Debnath, M. L.; Hope, C. E.; Isanski, B. A.; Hamilton, R. L.; DeKosky, S. T. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease Brain 2008, 131, 1630-1645 (Pubitemid 351806448)
190. Chang, E.; Congdon, E. E.; Honson, N. S.; Duff, K. E.; Kuret, J. Structure-activity relationship of cyanine tau aggregation inhibitors J. Med. Chem. 2009, 52, 3539-3547
191. Schafer, K. N.; Murale, D. P.; Kim, K.; Cisek, K.; Kuret, J.; Churchill, D. G. Structure-activity relationship of cyclic thiacarbocyanine tau aggregation inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 3273-3276
192. van Kan, H. J.; Groeneveld, G. J.; Kalmijn, S.; Spieksma, M.; van den Berg, L. H.; Guchelaar, H. J. Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis Br. J. Clin. Pharmacol. 2005, 59, 310-313 (Pubitemid 40388086)
193. Milane, A.; Fernandez, C.; Vautier, S.; Bensimon, G.; Meininger, V.; Farinotti, R. Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood-brain barrier J. Neurochem. 2007, 103, 164-173 (Pubitemid 47404226)
194. Hilal, H.; Taylor, J. A. Cyanine dyes for the detection of double stranded DNA J. Biochem. Biophys. Methods 2008, 70, 1104-1108
195. Clifton, J., 2nd; Leikin, J. B. Methylene blue Am. J. Ther. 2003, 10, 289-291
196. Johnson, I. D. Cellular Function Probes. In Current Protocols in Cytometry; Wiley Online Library, 2001; Chapter 4, Unit 4 4.
197. Hassan, H. M.; Fridovich, I. Intracellular production of superoxide radical and of hydrogen peroxide by redox active compounds Arch. Biochem. Biophys. 1979, 196, 385-395 (Pubitemid 10230154)
198. Zigman, S.; Gilman, P., Jr. Inhibition of cell division and growth by a redox series of cyanine dyes Science 1980, 208, 188-191 (Pubitemid 10072138)
199. Ballatore, C.; Brunden, K. R.; Piscitelli, F.; James, M. J.; Crowe, A.; Yao, Y.; Hyde, E.; Trojanowski, J. Q.; Lee, V. M.; Smith, A. B., 3rd. Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation J. Med. Chem. 2010, 53, 3739-3747
200. Ballatore, C.; Crowe, A.; Piscitelli, F.; James, M.; Lou, K.; Rossidivito, G.; Yao, Y.; Trojanowski, J. Q.; Lee, V. M.; Brunden, K. R.; Smith, A. B., 3rd. Aminothienopyridazine inhibitors of tau aggregation: evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo properties Bioorg. Med. Chem. 2012, 20, 4451-4461
201. Buchwald, P. Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations IUBMB Life 2010, 62, 724-731
202. Arkin, M. R.; Wells, J. A. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream Nat. Rev. Drug Discovery 2004, 3, 301-317 (Pubitemid 38499758)
203. Thiel, P.; Kaiser, M.; Ottmann, C. Small-molecule stabilization of protein-protein interactions: an underestimated concept in drug discovery? Angew. Chem., Int. Ed. 2012, 51, 2012-2018
204. Zhang, B.; Maiti, A.; Shively, S.; Lakhani, F.; McDonald-Jones, G.; Bruce, J.; Lee, E. B.; Xie, S. X.; Joyce, S.; Li, C.; Toleikis, P. M.; Lee, V. M.; Trojanowski, J. Q. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 227-231 (Pubitemid 40094457)
205. Lo Conte, L.; Chothia, C.; Janin, J. The atomic structure of protein-protein recognition sites J. Mol. Biol. 1999, 285, 2177-2198 (Pubitemid 29078179)
206. LeVine, H., 3rd. Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution Protein Sci. 1993, 2, 404-410
207. Klunk, W. E.; Pettegrew, J. W.; Abraham, D. J. Quantitative evaluation of Congo red binding to amyloid-like proteins with a beta-pleated sheet conformation J. Histochem. Cytochem. 1989, 37, 1273-1281 (Pubitemid 19186029)
208. Petric, A.; Johnson, S. A.; Pham, H. V.; Li, Y.; Ceh, S.; Golobic, A.; Agdeppa, E. D.; Timbol, G.; Liu, J.; Keum, G.; Satyamurthy, N.; Kepe, V.; Houk, K. N.; Barrio, J. R. Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 16492-16497
209. Reinke, A. A.; Gestwicki, J. E. Structure-activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility Chem. Biol. Drug Des. 2007, 70, 206-215 (Pubitemid 47305405)
210. Wolfe, L. S.; Calabrese, M. F.; Nath, A.; Blaho, D. V.; Miranker, A. D.; Xiong, Y. Protein-induced photophysical changes to the amyloid indicator dye thioflavin T Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 16863-16868
211. Krebs, M. R.; Bromley, E. H.; Donald, A. M. The binding of thioflavin-T to amyloid fibrils: localisation and implications J. Struct. Biol. 2005, 149, 30-37 (Pubitemid 40051399)
212. Klunk, W. E.; Debnath, M. L.; Pettegrew, J. W. Development of small molecule probes for the beta-amyloid protein of Alzheimer's disease Neurobiol. Aging 1994, 15, 691-698 (Pubitemid 24360159)
213. Inouye, H.; Kirschner, D. A. Alzheimer's beta-amyloid: insights into fibril formation and structure from Congo red binding Subcell. Biochem. 2005, 38, 203-224
214. Mukrasch, M. D.; Biernat, J.; von Bergen, M.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M. Sites of tau important for aggregation populate {beta}-structure and bind to microtubules and polyanions J. Biol. Chem. 2005, 280, 24978-24986 (Pubitemid 40934590)
215. Akoury, E.; Gajda, M.; Pickhardt, M.; Biernat, J.; Soraya, P.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M. Inhibition of tau filament formation by conformational modulation J. Am. Chem. Soc. 2013, 135, 2853-2862