BACE inhibitors as potential therapeutics for Alzheimer's disease

Recent Patents on CNS Drug Discovery

Volumn 2, Issue 3, 2007, Pages 188-199

  Evin, Geveviene ^a,c   Kenche, Vijaya B ^a,b,c  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c FLOREY INSTITUTE OF NEUROSCIENCE AND MENTAL HEALTH   (Australia)

Author keywords

secretase; A amyloid; Alzheimer's disease; Aspartyl protease; BACE1; Inhibitors

Indexed keywords

AMINE; AMYLOID BETA PROTEIN; ASPARTIC PROTEINASE; ASPARTIC PROTEINASE INHIBITOR; AZETIDINE DERIVATIVE; BENZAMIDE DERIVATIVE; BENZAMIDINE DERIVATIVE; BETA SECRETASE; BETA SECRETASE INHIBITOR; COUMARIN DERIVATIVE; EPIGALLOCATECHIN GALLATE; FLAVONOID; GAMMA SECRETASE; HYDROXYETHYLENE INHIBITOR; KMI 008; KMI 420; KMI 429; MORPHOLINE DERIVATIVE; OCTAPEPTIDE; OLIGOMER; PEPTIDE DERIVATIVE; PIPERAZINE DERIVATIVE; PIPERIDINE DERIVATIVE; PROTEIN PRECURSOR; PROTEINASE; PYRROLIDINE DERIVATIVE; QUINAZOLINE DERIVATIVE; STATIN; TETRADECAPEPTIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALZHEIMER DISEASE; BRAIN CORTEX; CLINICAL TRIAL; DRUG ACTIVITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG TARGETING; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME ASSAY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INHIBITION KINETICS; NERVE DEGENERATION; NONHUMAN; PATENT; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SINGLE DRUG DOSE; TRANSGENIC MOUSE;

ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ASPARTIC ENDOPEPTIDASES; ENZYME INHIBITORS; ETHYLENES; HUMANS;

EID: 36749073565     PISSN: 15748898     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488907782411783     Document Type: Review

References (137)

1. Thompson LA, Bronson JJ, Zusi FC. Progress in the discovery of BACE inhibitors. Curr Pharm Des 2005; 11: 3383-404.
2. Ghosh AK, Kumaragurubaran N, Tang J. Recent developments of structure based β-secretase inhibitors for Alzheimer's disease. Curr Top Med Chem 2005; 5: 1609-22.
3. Beher D, Graham SL. Protease inhibitors as potential disease-modifying therapeutics for Alzheimer's disease. Expert Opin Investig Drugs 2005; 14: 1385-409.
4. Cumming JN, Iserloh U, Kennedy ME. Design and development of BACE-1 inhibitors. Curr Opin Drug Discov Devel 2004; 7: 536-56.
5. John V. Human β-secretase (BACE) and BACE inhibitors: progress report. Curr Top Med Chem 2006; 6: 569-78.
6. Durham TB, Shepherd TA. Progress toward the discovery and development of efficacious BACE inhibitors. Curr Opin Drug Discov Devel 2006; 9: 776-91.
7. Schmidt B, Baumann S, Braun HA, Larbig G. Inhibitors and modulators of beta- and gamma-secretase. Curr Top Med Chem 2006; 6: 377-92.
8. Guo T, Hobbs DW. Development of BACE1 inhibitors for Alzheimer's disease. Curr Med Chem 2006; 13: 1811-29.
9. Selkoe DJ. Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nature Cell Biol 2004; 6: 1054-61.
10. Weidemann A, Eggert S, Reinhard FB, et al. A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 2002; 41: 2825-35.
11. Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest 2005; 115: 1449-1457.
12. Holsinger R, McLean C, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor β-secretase in Alzheimer's disease. Ann Neurol 2002; 51: 783-86.
13. Yang L, Lindholm K, Yan R, et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003; 9: 3-4.
14. Fukumoto H, Cheung B, Hyman B, Irizarry M. β-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002; 59: 1381-89.
15. Vassar R, Bennett BD, Babu-Khan S, et al. β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735-41.
16. Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 1999; 402: 537-40.
17. Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 1999; 402: 533-37.
18. Hussain I, Powell D, Howlett Dr, et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol Cell Neurosci 1999; 14: 419-27.
19. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc Natl Acad Sci USA 2000; 97: 1456-60.
20. Haniu M, Denis P, Young Y, et al. Characterization of Alzheimer's β-secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem 2000; 275: 21099-106.
21. Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science 2000; 290: 150-53.
22. Shi XP, Chen E, Yin KC, et al. The pro domain of β-secretase does not confer strict zymogen-like properties but does assist proper folding of the protease domain. J Biol Chem 2001; 276: 10366-73.
23. Benjannet S, Elagoz A, Wickham L, et al. Post-translational processing of β-secretase (β-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-β production. J Biol Chem 2001; 276: 10879-87.
24. Capell A, Steiner H, Willem M, et al. Maturation and pro-peptide cleavage of β-secretase J Biol Chem 2000; 275: 30849-54.
25. Huse JT, Pijak DS, Leslie GJ, Lee VM, Doms RM. Maturation and endosomal targeting of β-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease β-secretase. J Biol Chem 2000; 275: 33729-37.
26. Bennett BD, Denis P, Haniu M, et al. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's β-secretase. J Biol Chem 2000; 275: 37712-17.
27. Creemers JW, Ines Dominguez D, Plets E, et al. Processing of β-secretase by furin and other members of the proprotein convertase family. J Biol Chem 2001; 276: 4211-17.
28. Charlwood J, Dingwall C, Matico R, et al. Characterization of the glycosylation profiles of Alzheimer's β-secretase protein Asp-2 expressed in a variety of cell lines. J Biol Chem 2001; 276: 16739-48.
29. Scholefield Z, Yates EA, Wayne G, Amour A, Mcdowell W, Turnbull JET. Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase. J Cell Biol 2003; 63: 97-107.
30. Westmeyer GG, Willem M, Lichtenthaler SF, et al. Dimerization of β-site β-amyloid precursor protein-cleaving enzyme. J Biol Chem 2004; 279: 53205-12.
31. Schmechel A, Strauss M, Schlicksupp, A, et al. Human BACE forms dimers and colocalizes with APP. J Biol Chem 2004; 279: 39710-17.
32. Patel S, Vuillard L, Cleasby A, Murray CW, Yon J. Apo and inhibitor complex structures of BACE (β-secretase). J Mol Biol 2004; 343: 407-16.
33. Wang W, Reichert P, Beyer BM, et al. Crystallization of glycosylated human BACE protease domain expressed in Trichoplusia ni. Biochim Biophys Acta 2004; 1698: 255-59.
34. He X, Li F, Chang WP, Tang J. GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem 2004; 280: 11696-703.
35. Von Amim CA, Tangredi MM, Peltan ID, et al. Demonstration of BACE (β-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy. J Cell Sci 2004; 117: 5437-45.
36. Shiba T, Kametaka S, Kawasaki M, et al. Insights into the phosphoregulation of β-secretase sorting signal by the VHS domain of GGA1. Traffic 2004; 5: 437-48.
37. Tesco G, Koh YH, Kang EL, et al. Depletion of GGA3 stabilizes BACE and enhances β-secretase activity. Neuron 2007; 54: 721-37.
38. Wahle T, Thal DR, Sastre M, et al. GGA1 is expressed in the human brain and affects the generation of amyloid β-peptide. J Neurosci 2006; 26: 12838-46.
39. Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished b-amyloid generation. Nat Neurosci 2001; 4: 231-32.
40. Cai H, Wang Y, McCarthy D, et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci 2001; 4: 233-34.
41. Hartmann D, Tournoy J, Saftig P, Annaert W, De Strooper B. Implication of APP secretases in notch signaling. J Mol Neurosci 2001; 17: 171-81.
42. Evin G, Sernee MF, Masters CL. Inhibition of γ-secretase as a therapeutic intervention for Alzheimer's disease: prospects, limitations and strategies. CNS Drugs 2006; 20: 351-72.
43. Li Q, Sudhof TC. Cleavage of amyloid-β precursor protein and amyloid-β precursor-like protein by BACE 1. J Biol Chem 2004; 279: 10542-50.
44. Pastorino L, Ikin AF, Lamprianou S, et al. BACE (β-sceretase) modulates the processing of APLP2 in vivo. Mol Cell Neurosci 2 2004; 25: 642-49.
45. Kitazume S, Nakagawa K, Oka R, et al. in vivo Cleavage of alpha2, 6-sialyltransferase by Alzheimer β-secretase. J Biol Chem 2005; 280: 8589-95.
46. Lichtenthaler SF, Dominguez DI, Westmeyer GG, et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem 2003; 78: 48713-19.
47. Von Arnim CA, Kinoshita A, Peltan ID, et al. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J Biol Chem 2005; 280: 17777-85.
48. Willem M, Garratt AN, Novak B, et al. Control of peripheral nerve myelination by the β-secretase BACE1. Science 2006; 314: 664-66.
49. Hu X, Hicks CW, He W, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006; 9: 1520-25.
50. Kim DY, Carey BW, Wang H, et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol 2007; doi:10.1038/ ncb1602 (published online 18/06/07).
51. Ohno M, Sametsky EA, Younkin LH, et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 2004; 41: 27-33.
52. Harrison SM, Harper AJ, Hawkins J. BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci 2003; 24: 646-55.
53. Dominguez D, Tournoy J, Hartmann D, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 2005; 280: 30797-806.
54. Singer O, Marr Ra, Rockenstein E, et al. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 2005; 8: 1343-49.
55. Eder J, Hommel U, Cumin F, Martoglio B, Gerhartz B. Aspartic proteases in drug discovery. Curr Pharm Des 2007; 13: 271-85.
56. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc Natl Acad Sci USA 2000; 97: 1456-60.
57. Kunimoto S, Aoyagi T, Morishima H, Takeuchi T, Umezawa H. Mechanism of inhibition of pepsin by pepstatin. J Antibiot (Tokyo) 1972; 25: 251-55.
58. Hu B, Fan KY, Bridges K, et al. Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors. Bioorg Med Chem Lett 2004; 14: 3457-60.
59. Bridges KG, Chopra R, Lin L, et al. A novel approach to identifying β-secretase inhibitors: bis-statine peptide mimetics discovered using structure and spot synthesis. Peptides 2006; 27: 1877-85.
60. Schostarez, H.J., Chrusciel, R.A.: WO03006021 (2003).
61. Peters, S., Fuchs, K., Eickmeier, C., Stransky, W., Dorner-Ciossek, C., Handschuh, S., Nar, H., Klinder, K., Kostka, M.: WO06050862 (2006).
62. Turner RT 3rd, Koelsch G, Hong L, et al. Subsite specificity of memapsin 2 (β-secretase): implications for inhibitor design. Biochemistry 2001; 40: 10001-06.
63. Chang WP, Koelsch G, Wong S, et al. in vivo Inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors. J Neurochem 2004; 89: 1409-16.
64. Ghosh AK, Devasamudram T, Hong L, et al. Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase). Bioorg Med Chem Lett 2005; 15: 15-20.
65. Ghosh, A.K., Kumaragurubaran, N., Liu, C., Devasamudram, T., Lei, H., Swanson, L., Ankala, S.T. J., Bilcer, G.: WO06110668 (2006).
66. Ghosh, A., Lei, H., Devasamudram, T., Liu, C., Bilcer, G.: WO06034277 (2006).
67. Ghosh AK, Kumaragumbaran N, Hong L, et al. Design, synthesis, and X-ray structure of potent memapsin 2 (β-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem 2007; 50: 2399-407.
68. Shuto D, Kasai S, Kimura T, et al. KMI-008, a novel β-secretase inhibitor containing a hydroxymcthylcarbonyl isostcrc, as a transition-state mimic: design and synthesis of substrate-based octapeptides. Bioorg Med Chem Lett 2003; 13: 4273-76.
69. Kimura T, Shuto D, Kasai S, et al. KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine. Bioorg Med Chem Lett 2004; 14: 1527-31.
70. Kimura T, Shuto D, Hamada Y, et al. Design and synthesis of highly active Alzheimer's β-sccretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability. Bioorg Med Chem Lett 2005; 15: 211-15.
71. Hamada Y, Igawa N, Ikari H, et al. β-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells. Bioorg Mod Chem Lett 2006; 16: 4354-59.
72. Asai M, Hattori C, Iwata N, et al. The novel β-secretase inhibitor KMI-429 reduces amyloid b peptide production in amyloid precursor protein transgcnic and wild-type mice. J Neurochem. 2006; 96: 533-40.
73. Kimura T, Hamada Y, Stochaj M, et al. Design and synthesis of potent β-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres. Bioorg Med Chem Lett 2006; 6: 2380-86.
74. Ziora Z, Kasai S, Hidaka K, et al. Design and synthesis of BACE1 inhibitors containing a novel norstatine derivative (2R, 3R)-3-amino-2-hydroxy4-phenylthio) butyric acid. Bioorg Med Chem Lett 2007; 17: 1629-33.
75. Freskos, J., Brown, D.L., Fang, L., Fobian, Y.M., Varghese, J., Romero, A.G.: WO02098849 (2002).
76. Tamamura H, Kato T, Otaka A, Fji N. Synthesis of potent β-secretase inhibitors containing a hydroxyethylamine dipeptide, isostere and their structure-activity relationship studies. Org Biomol Chem 2003; 1: 2468-73.
77. Vuillard, L.M.M., Patel, S.J., Yon, J.R., Cleasby, A., Hamilton, B.J., Shah, A.: WO04011641 (2004).
78. Beck, J.P., Gailunas, A., Hom, R., Jagodzinska, J.B.V., Maillaird, M.: WO02002520 (2002).
79. Aquino, J., John, V., Tucker, J.A., Hom, R., Pulley, S., Tenbrink, R.: WO04094384 (2004).
80. Demont, E.H., Faller, A., Macpherson, D.T., Milner, P.H., Naylor, A., Redshaw, S., Stanway, S.J., Vesey, D.R., Walter, D.S.: WO04050619 ( 2004).
81. Uchikawa, O., Aso, K., Koike, T., Tarui, N., Hirai, K.: WO04014843 ( 2004).
82. Tenbrink, R., Maillard, M., Wapehoski, M.: WO03050073 (2003).
83. Sealy, J., Hom, R., John, V., Probst, G., Tung, J.S.: WO06010094 ( 2006).
84. John, V., Maillard, M., Jagodzinska, B., Aquino, J., Probst, G., Tung, J.S.: WO06010095 (2006).
85. Demont, E.H., Redshaw, S., Walter, D.S.: WO04080376 (2004).
86. Hussain I, Hawkins J, Harrison D, et al. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases β-cleavage of amyloid precursor protein and amyloid-β production in vivo. J Neurochem 2007; 100: 802-09.
87. Redshaw, S., Demont, E.H., Walter, D.S., Vesey, D.R.: WO05058915 ( 2005).
88. Auberson, Y., Betschart, C., Glatthar, R., Laumen, K, Machauer, R., Tintelnot-Blomley, M., Troxler, T.J., Voenstra, S.J.: WO2005049585 ( 2005).
89. John, V., Maillaird, M., Fang, L.J.T., Brogley, L., Aquino, J., Bowers, S., Probst, G., Tung, J.: WO05087714 (2005).
90. Coburn, C.A., Stachel, S.J., Vacca, J.P.: US20060264416 (2006).
91. Coburn, C.A., Stachel, S,J., Vacca, J.P.: WO05004802 (2005).
92. Freskos JN, Fobian YM, Benson TE, et al. Design of potent inhibitors of human β-secretase. Part 1. Bioorg Med Chem Lett 2007; 17: 73-77.
93. Freskus JN, Fobian YM, Benson TE, et al. Design of potent inhibitors of human β-secretese. Part 2. Bioorg Med Chem Lett 2007; 17: 78-81.
94. Thompson, R.C., Wilkie, S., Stack, D.R., Vanmetereldon, E., Shi, Q., Britton, T.C., Audi, A.J.E., Reel, J.K., Mabr, Y.T.E., Dressman, B.A., Cwi, C.L., Henry, S.S., McDaniel, S.L., Stucky, R.D., Porter, W. J.: US20050192265 (2005).
95. Bueno Melendo, A.B., Chen, S-H., Erickson, J.A., Gonzales-Garcia, M.R., Guo, D., Marcos Llorente, A., Me Carthy, J.R., Shepherd, T.A., Bender, D.M., Sheehan, S.M., Yip, Y.Y.M.: WO05108391 (2005).
96. Cumming, J.N., Iserloh, U., Stamford, A., Strickland, C., Voigt, J.H., Wu, Y., Huang, Y., Xia, Y., Chackalamannil, S., Guo, T., Hobbs, D.W., Le, T.X.H., Lowrie, J.F., Saionz, K.W., Babu, S.D.: WO05016876 (2005).
97. Cumming, J.N., Huang, Y., Li, G., Iserloh, U., Stamford, A., Strickland, C., Voigt, J.H., Wu, Y., Pan, J., Gun, T., Hobbs, D.W., Le, T.X.H., Lowrie, J.F.: WO05014540 (2005).
98. Hom, R., Fang, L., John, V., Truong, A.U.: WO06026533 (2006).
99. Daily, R.D., Shepherd, T.A., Bender, D.M., Rojo Garcia, M.I.: WO05108358 (2005).
100. Stamford, A.W, Huang, Y., Li, G., Strickland, C.O., Voig J.H.: WO06014944 (2006).
101. Durham, T.B., Hahn, P.J., Kohn, T.J., Mccarthy, J.R., Broughton, H.B., Dally, R.D., Gonzalez-Garcia, M.R., Henry, K.J. Jr., Shepherd, T.A., Erickson, J.A., Bueno-Melendo, A.B.: WO06034093 (2006).
102. Schostarez, H.J., Chrusciel, R.A.: WO03006453 (2003).
103. Yang W, Lu W, Lu Y, et al. Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1. J Med Chem 2006; 49: 39-42.
104. Stachel SJ, Coburn CA, Sankaranarayanan S, et al. Macrocyclic inhibitors of β-secretase: functional activity in an animal model. J Med Chem 2006; 49: 6147-50.
105. Stauffer SR, Stanton MG, Gregro AR, et al. Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation. Bioorg Med Chem Left 2007; 15: 1788-92.
106. Stanton MG, Stauffe SF, Gregro ARG, et al. Discovery of isonicotinamide derived-secretase Inhibitors: in vivo reduction of β-amyloid J Med Chem 2007; DOI: 10. 1021/jm070272d (published online 21/06/07).
107. Coburn CA, Stachel SI, Jones KG, et al. BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteres. Bioorg Med Chem Lett 2006; 16: 3635-38.
108. Szelke M, Leckie B, Hallett A, et al. Potent new inhibitors of human renin. Nature 1982; 299: 555-57.
109. Manzenrieder F, Frank AO, Huber T, Dorner-Ciossek C, Kessler H. Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human β-secretase (BACE-1). Bioorg Med Chem 2007; 15: 4136-43.
110. Coburn CA, Stachel SJ, Li YM, et al. Identification of a small molecule nonpeptide active site β-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases. J Med Chem 2004; 47: 6117-19.
111. Stachel SJ, Coburn CA, Steele TG, et al. Structure-based design of potent and selective cell-permeable inhibitors of human β-secretase (BACE-1). J Med Chem 2004; 47: 6447-50.
112. Coburn, C.A., Stachel, S.J., Vacca, J.P.: WO04062625 (2004).
113. Coburn, C., Stachel, S.J., Vacca, J.P.: WO05018545 (2005).
114. Cole DC, Manas ES, Stock JR, et al. Acylguanidines as small-molecule β-secretase inhibitors. J Med Chem 2006; 49: 6158-61.
115. Hu, B.: US20060183943 (2006).
116. Fobare, W.F., Solvibile, W.R.J.: US20060183792 (2006).
117. Geiritz, S.C., Good A.C., ThompsonIII, L.A., Zhaj, W., Shi, S., Zhu, S.: US 20070015754 (2007).
118. Thompson, L.A., Shi, F.J., Zusi, C., Dee, M.F., Macor, J.E.: US 20070049589 (2007).
119. Malamas, M.S., Erdei, J.J., Gunawan, I.S., Barnes, K.D., Johnson, M.R., Hui, Y.: US20050282826 (2005).
120. Malamas, M.S., Erdei, J.J., Gunawan, I.S., Zhou, P., Yan, Y., Quagliato, DA.: US20050282825 (2005).
121. Zhu, Z., Mckittrick, B., Sun, Z-Y., Ye, Y.C., Voigt, J.H., Strickland, C., Smith, E.M., Stamford, A., Greenlee, W.J., Wu, Y., Iserloh, U., Mazzola, R., Caldwell, J., Cumming, J., Wang, L., Goo, T., Le, T.X.H., Saionz, K.W., Babu, S.D. Hunter, R.C.: WO05058311 (2005).
122. Baxter, E., Bischoff, F.P., Boyd, R., Braeken, M., Coats, S., Huang, Y., Jordan, A., Luo, C., Mercken, M.H., Reynolds, C.H., Ross, T.M., Tounge, B.A., Schulz, M., Do Winter, H.L.J., Pieters, S.M.A., Reitz, A. B.: WO06017836 (2006).
123. Baxter, E., Boyd, R., Coats, S., Jordan, A., Reitz, A., Reynolds, C.H., Scott, M, Schulz, M., De Winter, H.L.J.: WO06017844 (2006).
124. Albert, J., Andisik, D., Arnold, J., Brown, D., Callaghan, O., Campbell, J., Carr, R., Chessari, G., Congreve, M., Edwards, P., Empfield, J., Frederickson, M., Koether, G., Krumarine, J., Mauger, R., Patel, S., Murray, C., Sylvester, M., Throner, S.: WO06041405 (2006).
125. Albert, J., Andisik, D., Arnold, J., Brown, D., Callaghan, O., Carr, R., Chessari, G., Congreve, M., Empfield, J., Frederickson, M., Koether, G., Krumrine, J., Manger, R., Murray, C., Patel, S., Sylvester, M., Throner, S.: WO06041404 (2006).
126. Coburn, C.A., Espeseth, A.S., Stachel, S.J., Olsen, D.B., Hazuda, D.J. Holloway, M.K.: WO05097767 (2005).
127. Barrow, J, C., Coburn, C, A., Egbertson, M, S., Mcgaughey, G, B., Mcwherter, M, A., Neilson, L.A., Selnick, H, G., Stauffer, S, R., Yang, Z-Q., Yang, W., Lu, W., Fahr, B., Rittle, K.E.: WO06044497 (2006).
128. Coburn, C.A., Egbertson, M.S., Graham, S.L., Mcgaughey, G.B., Stauffer, S. R., Rajapakse, H.A., Nantermet, P.G., Stachel, S.R., Yang, W., Lu, W., Fahr, B.: WO07011833 (2007).
129. Godel, T., Hilpert, H., Humm, R., Rogers-Evans, M., Rombach, D., Stahl, C.M., Weiss, P., Wostl, W.D.: WO05058857 (2005).
130. Larbig G, Schmidt B. Synthesis of tetramic, and tetronic acids as β-secretase inhibitors. J Comb Chem 2006; 8: 480-90.
131. Garino C, Tomita T, Pietrancosta N, et al. Naphthyl and cournarinyl biarylpiperazine derivatives as highly potent human β-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays. J Med Chem 2006; 49: 4275-85.
132. Garino C, Pietrancosta N, Laras Y, et al. BACE-1 inhibitory activities of new substituted phenyl-piperazine coupled to various heterocycles: chromene, coumarin and quinoline. Bioorg Med Chem Lett 2006; 16: 1995-99.
133. Huang D, Luthi U, Kolb P, Cecchini M, Barberis A, Caflisch A. in silico Discovery of β-secretase inhibitors. J Am Chem Soc 2006; 128: 5436-43.
134. Castillo, G., Snow, A.D., Choi, P.Y.: WO01049307 (2001).
135. Jeon SY, Bae & Seong YH, Song KS. Green tea catechins as a BACE1 (β-secretase) inhibitor. Bioorg Med Chem Lett 2003; 13: 3905-08.
136. Rezai-Zadeh K, Shytte D, Sun N, et al. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 2005; 25: 8807-14.
137. Lee HJ, Soong YH, Bae KH, et al. β-secretase (BACE1) inhibitors from Sanguisorbae Radix. Arch Pharm Res 2005; 28: 799-803.