γ-Secretase as a therapeutic target for the treatment of Alzheimer's disease

Current Pharmaceutical Design

Volumn 11, Issue 26, 2005, Pages 3363-3382

  Churcher, Ian ^a   Beher, Dirk ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; AMYLOID BETA PROTEIN; ASPARTIC PROTEINASE; BENZODIAZEPINE DERIVATIVE; CALPASTATIN; CAPROLACTAM; FLURBIPROFEN; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; IBUPROFEN; INDOMETACIN; LY 411575; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; NOTCH RECEPTOR; PIPERIDINE DERIVATIVE; PROTEINASE INHIBITOR; STATINE DERIVATIVE; SULFAMIDE DERIVATIVE; SULFONAMIDE; SULFONE DERIVATIVE; SULINDAC SULFIDE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; DRUG BINDING; DRUG DOSE REGIMEN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NEUROTOXICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN SYNTHESIS; REVIEW;

EID: 24944439990     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161205774370771     Document Type: Review

References (240)

1. Alzheimer A. Allg Z Psychiatrie Psychisch -Gerichtl Med 1907; 64: 146-8.
2. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA 1988; 85: 4051-5.
3. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 1992; 8: 159-68.
4. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998; 95: 7737-41.
5. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998; 393: 702-5.
6. Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH. Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett 1992; 147: 58-62.
7. Yang SD, Song JS, Yu JS, Shiah SG. Protein kinase FA/GSK-3 phosphorylates tau on Ser235-Pro and Ser404-Pro that are abnormally phosphorylated in Alzheimer's disease brain. J Neurochem 1993; 61: 1742-7.
8. Baumann K, Mandelkow EM, Biernat J, Piwnica-Worms H, Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett 1993; 336: 417-24.
9. Drewes G, Lichtenberg-Kraag B, Doring F, Mandelkow EM, Biernat J, Goris J, et al. Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J 1992; 11: 2131-8.
10. Lu Q, Soria JP, Wood JG. p44mpk MAP kinase induces Alzheimer type alterations in tau function and in primary hippocampal neurons. J Neurosci Res 1993; 35: 439-44.
11. Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 1997; 89: 297-308.
12. Nishimura I, Yang Y, Lu B. PAR-1 Kinase Plays an Initiator Role in a Temporally Ordered Phosphorylation Process that Confers Tau Toxicity in Drosophila. Cell 2004; 116: 671-82.
13. Ksiezak-Reding H, Pyo HK, Feinstein B, Pasinetti GM. Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta 2003; 1639: 159-68.
14. Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett 1997; 409: 57-62.
15. Roder HM, Eden PA, Ingram VM. Brain protein kinase PK40erk converts TAU into a PHF-like form as found in Alzheimer's disease. Biochem Biophys Res Commun 1993; 193: 639-47.
16. Reynolds CH, Betts JC, Blackstock WP, Nebreda AR, Anderton BH. Phosphorylation sites on tau identified by nanoelectrospray mass spectrometry: differences in vitro between the mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and P38, and glycogen synthase kinase-3beta. J Neurochem 2000; 74: 1587-95.
17. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992; 256: 184-5.
18. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885-90.
19. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985; 82: 4245-9.
20. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987; 325: 733-6.
21. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, et al. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 1992; 359: 322-5.
22. Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 1998; 273: 27765-7.
23. Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA 1999; 96: 3922-7.
24. Weidemann A, Konig G, Bunke D, Fischer P, Salbaum JM, Masters CL, et al. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell 1989; 57: 115-26.
25. Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F, et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet 1992; 1: 218-21.
26. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 1990; 248: 1124-6.
27. Davis J, Van Nostrand WE. Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. Proc Natl Acad Sci USA 1996; 93: 2996-3000.
28. Melchor JP, McVoy L, Van Nostrand WE. Charge alterations of E22 enhance the pathogenic properties of the amyloid beta-protein. J Neurochem 2000; 74: 2209-12.
29. Murakami K, Irie K, Morimoto A, Ohigashi H, Shindo M, Nagao M, et al. Neurotoxicity and physicochemical properties of Abeta mutant peptides from cerebral amyloid angiopathy: implication for the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. J Biol Chem 2003; 278: 46179-87.
30. Price DL, Sisodia SS, Borchelt DR. Genetic neurodegenerative diseases: the human illness and transgenic models. Science 1998; 282: 1079-83.
31. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991; 349: 704-6.
32. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, et al. Early-onset alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 1991; 353: 844-6.
33. Naruse S, Igarashi S, Kobayashi H, Aoki K, Inuzuka T, Kaneko K, et al. Mis-sense mutation Val - Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet 1991; 337: 978-9.
34. Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 1991; 254: 97-9.
35. Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1992; 1: 345-7.
36. Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, et al. A new pathogenic mutation in the APP gene (1716V) increases the relative proportion of A beta 42(43). Hum Mol Genet 1997; 6: 2087-9.
37. Kwok JB, Li QX, Hallupp M, Whyte S, Ames D, Beyreuther K, et al. Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol 2000; 47: 249-53.
38. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995; 269: 973-7.
39. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, et al. A familial Alzheimer's disease locus on chromosome 1. Science 1995; 269: 970-3.
40. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995; 376: 775-8.
41. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995; 375: 754-60.
42. Hardy J. The Alzheimer family of diseases: many etiologies, one pathogenesis? Proc Natl Acad Sci USA 1997; 94: 2095-7.
43. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci 1997; 20: 154-9.
44. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 1992; 360: 672-4.
45. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735-41.
46. Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L Jr, Eckman C, et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 1994; 264: 1336-40.
47. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 1996; 2: 864-70.
48. Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, et al. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med 1996; 2: 1146-50.
49. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 1996; 17: 1005-13.
50. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 1996; 383: 710-3.
51. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 1997; 3: 67-72.
52. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999; 14: 419-27.
53. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999; 402: 537-40.
54. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 1999; 402: 533-7.
55. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA 2000; 97: 1456-60.
56. Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, et al. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001; 4: 233-4.
57. Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, Murdock PR, et al. ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Mol Cell Neurosci 2000; 16: 609-19.
58. Saunders AJ, Kim T-W, Tanzi RE. BACE maps to chromosome 11 and a BACE homolog, BACE2, reside in the obligate Down Syndrome region of chromosome 21. Science 1998; 286: 1255a.
59. Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc Natl Acad Sci USA 2000; 97: 9712-7.
60. Yan R, Munzner JB, Shuck ME, Bienkowski MJ. BACE2 functions as an alternative alpha-secretase in cells. J Biol Chem 2001; 276: 34019-27.
61. Fluhrer R, Capell A, Westmeyer G, Willem M, Hartung B, Condron MM, et al. A non-amyloidogenic function of BACE-2 in the secretory pathway. J Neurochem 2002; 81: 1011-20.
62. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, et al. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 2001; 4: 231-2.
63. Haass C. Take five-BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation. EMBO J 2004; 23: 483-8.
64. Selkoe DJ. Folding proteins in fatal ways. Nature 2003; 426: 900-4.
65. De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003; 38: 9-12.
66. Martoglio B, Golde TE. Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs. Hum Mol Genet 2003; 12 Spec No 2: R201-R206.
67. Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 2003; 26: 565-97.
68. Medina M, Dotti CG. RIPped out by presenilin-dependent gamma-secretase. Cell Signal 2003; 15: 829-41.
69. Tsai JY, Wolfe MS, Xia W. The search for gamma-secretase and development of inhibitors. Curr Med Chem 2002; 9: 1087-106.
70. Kornilova AY, Wolfe MS. Secretase inhibitors for Alzheimer's disease. Annu Rep Med Chem 2003; 38: 41-50.
71. Schmidt B. Aspartic proteases involved in Alzheimer's disease. ChemBioChem 2003; 4: 366-78.
72. Thinakaran G, Borchelt DR, Lee MK, Stunt HH, Spitzer L, Kim G, et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996; 17: 181-90.
73. Doan A, Thinakaran G, Borchelt DR, Slunt HH, Ratovitsky T, Podlisny M, et al. Protein topology of presenilin 1. Neuron 1996; 17: 1023-30.
74. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, et al. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 1996; 93: 14940-4.
75. Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL, et al. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 1997; 272: 28415-22.
76. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391: 387-90.
77. Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, et al. L-685, 458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid β-protein precursor γ-secretase activity. Biochemistry 2000; 39: 8698-704.
78. Wolfe MS, Citron M, Diehl TS, Xia W, Donkor IO, Selkoe DJ. A substrate-based difluoro ketone selectively inhibits Alzheimer's gamma-secretase activity. J Med Chem 1998; 41: 6-9.
79. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Rahmati T, et al. Peptidomimetic probes and molecular modeling suggest that Alzheimer's gamma-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 1999; 38: 4720-7.
80. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999; 398: 513-7.
81. Steiner H, Kostka M, Romig H, Basset G, Pesold B, Hardy J, et al. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat Cell Biol 2000; 2: 848-51.
82. Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith JEjr, et al. Presenilin-1 and 2 are molecular targets for gamma secretase inhibitors. J Biol Chem 2000; 275: 34086-91.
83. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, et al. Photoactivated γ-secretatase inhibitors directed to the active site covalently label presenilin 1. Nature 2000; 405: 689-94.
84. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, et al. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat Cell Biol 2000; 2: 428-34.
85. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000; 407: 48-54.
86. Goutte C, Tsunozaki M, Hale VA, Priess JR. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci USA 2002; 99: 775-9.
87. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, et al. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002; 3: 85-97.
88. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol 2003; 5: 486-8.
89. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003; 422: 438-41.
90. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. gamma-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2. Proc Natl Acad Sci USA 2003; 100: 6382-7.
91. Shirotani K, Edbauer D, Capell A, Schmitz J, Steiner H, Haass C. Gamma-secretase activity is associated with a conformational change of nicastrin. J Biol Chem 2003; 278: 16474-7.
92. LaVoie MJ, Fraering PC, Ostaszewski BL, Ye W, Kimberly WT, Wolfe MS, et al. Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin. J Biol Chem 2003; 278: 37213-22.
93. Hu Y, Fortini ME. Different cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex. J Cell Biol 2003; 161: 685-90.
94. Fortna RR, Crystal AS, Morais VA, Pijak DS, Lee VM, Doms RW. Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the gamma-secretase complex. J Biol Chem 2004; 279: 3685-93.
95. Crystal AS, Morais VA, Pierson TC, Pijak DS, Carlin D, Lee VM, et al. Membrane topology of gamma-secretase component PEN-2. J Biol Chem 2003; 278: 20117-23.
96. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Complex N-linked Glycosylated Nicastrin Associates with Active gamma -Secretase and Undergoes Tight Cellular Regulation. J Biol Chem 2002; 277: 35113-7.
97. Beher D, Fricker M, Nadin A, Clarke EE, Wrigley JD, Li YM, et al. In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand. Biochemistry 2003; 42: 8133-42.
98. Herreman A, Van Gassen G, Bentahir M, Nyabi O, Craessaerts K, Mueller U, et al. gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. J Cell Sci 2003; 116: 1127-36.
99. Capell A, Grunberg J, Pesold B, Diehlmann A, Citron M, Nixon R, et al. The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J Biol Chem 1998; 273: 3205-11.
100. Yu G, Chen F, Levesque G, Nishimura M, Zhang DM, Levesque L, et al. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J Biol Chem 1998; 273: 16470-5.
101. Beher D, Wrigley JD, Nadin A, Evin G, Masters CL, Harrison T, et al. Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology. J Biol Chem 2001; 276: 45394-402.
102. Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, et al. Presenilin 1 is linked with gamma -secretase activity in the detergent solubilized state. Proc Natl Acad Sci USA 2000; 97: 6138-43.
103. Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, et al. A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci USA 2003; 100: 13075-80.
104. Edbauer D, Winkler E, Haass C, Steiner H. Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Proc Natl Acad Sci USA 2002; 99: 8666-71.
105. Steiner H, Winkler E, Edbauer D, Prokop S, Basset G, Yamasaki A, et al. PEN-2 is an integral component of the gamma -secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem 2002; 277: 39062-5.
106. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 2002; 296: 2215-8.
107. Nyborg AC, Kornilova AY, Jansen K, Ladd TB, Wolfe MS, Golde TE. Signal peptide peptidase forms a homodimer that is labeled by an active site directed gamma-secretase inhibitor. J Biol Chem 2004; 279: 15153-60.
108. Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P, et al. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 2001; 32: 579-89.
109. Tian G, Sobotka-Briner CD, Zysk J, Liu X, Birr C, Sylvester MA, et al. Linear non-competitive inhibition of solubilized human gamma -secretase by pepstatin A methylester, L-685458, sulfonamides and benzodiazepines. J Biol Chem 2002; 277: 31499-505.
110. Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ, et al. Activity-dependent isolation of the presenilin-gamma -secretase complex reveals nicastrin and a gamma substrate. Proc Natl Acad Sci USA 2002; 99: 2720-5.
111. Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, et al. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 2002; 21: 5408-16.
112. Lichtenthaler SF, Beher D, Grimm HS, Wang R, Shearman MS, Masters CL, et al. The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain. Proc Natl Acad Sci USA 2002; 99: 1365-70.
113. Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, Condron MM, et al. Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2001; 2: 835-41.
114. Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y. Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch. J Biol Chem 2001; 276: 35235-8.
115. Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, 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.
116. Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000; 100: 391-8.
117. Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, et al. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J Biol Chem 2002; 277: 44754-9.
118. Scheinfeld MH, Ghersi E, Laky K, Fowlkes BJ, D'Adamio L. Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription. J Biol Chem 2002; 277: 44195-201.
119. Eggert S, Paliga K, Soba P, Evin G, Masters CL, Weidemann A, et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha -, beta -, gamma -, and epsilon -like cleavages. Modulation of APLP-1 processing by N-glycosylation. J Biol Chem 2004; 279: 18146-56.
120. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999; 398: 518-22.
121. Six E, Ndiaye D, Laabi Y, Brou C, Gupta-Rossi N, Israel A, et al. The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proc Natl Acad Sci USA 2003; 100: 7638-43.
122. LaVoie MJ, Selkoe DJ. The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem 2003; 278: 34427-37.
123. Ikeuchi T, Sisodia SS. The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage. J Biol Chem 2003; 278: 7751-4.
124. Ni CY, Murphy MP, Golde TE, Carpenter G. gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001; 294: 2179-81.
125. Lee HJ, Jung KM, Huang YZ, Bennett LB, Lee JS, Mei L, et al. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J Biol Chem 2002; 277: 6318-23.
126. Schulz JG, Annaert W, Vandekerckhove J, Zimmermann P, De Strooper B, David G. Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling. J Biol Chem 2003; 278: 48651-7.
127. Kim DY, Ingano LA, Kovacs DM. Nectin-1alpha, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/gamma-secretase-like cleavage. J Biol Chem 2002; 277: 49976-81.
128. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, et al. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003; 114: 635-45.
129. Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, et al. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 2002; 21: 1948-56.
130. Taniguchi Y, Kim SH, Sisodia SS. Presenilin-dependent "gamma-secretase" processing of deleted in colorectal cancer (DCC). J Biol Chem 2003; 278: 30425-8.
131. Jung KM, Tan S, Landman N, Petrova K, Murray S, Lewis R, et al. Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor. J Biol Chem 2003; 278: 42161-9.
132. May P, Reddy YK, Herz J. Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J Biol Chem 2002; 277: 18736-43.
133. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995; 268: 225-32.
134. Washburn T, Schweighoffer E, Gridley T, Chang D, Fowlkes BJ, Cado D, et al. Notch activity influences the alphabeta versus gammadelta T cell lineage decision. Cell 1997; 88: 833-43.
135. Pui JC, Allman D, Xu L, DeRocco S, Karnell FG, Bakkour S, et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 1999; 11: 299-308.
136. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA 1998; 95: 8108-12.
137. Lindsell CE, Shawber CJ, Boulter J, Weinmaster G. Jagged: a mammalian ligand that activates Notch1. Cell 1995; 80: 909-17.
138. Fehon RG, Kooh PJ, Rebay I, Regan CL, Xu T, Muskavitch MA, et al. Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 1990; 61: 523-34.
139. Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 1991; 67: 687-99.
140. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 2000; 5: 207-16.
141. Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, et al. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 2000; 5: 197-206.
142. Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998; 393: 382-6.
143. Lewis HD, Perez Revuelta BI, Nadin A, Neduvelil JG, Harrison T, Pollack SJ, et al. Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages. Biochemistry 2003; 42: 7580-6.
144. Higaki J, Quon D, Zhong Z, Cordell B. Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 1995; 14: 651-9.
145. Steinhilb ML, Turner RS, Gaut JR. The protease inhibitor, MG132, blocks maturation of the amyloid precursor protein Swedish mutant preventing cleavage by beta-secretase. J Biol Chem 2001; 276: 4476-84.
146. Higaki JN, Chakravarty S, Bryant CM, Cowart LR, Harden P, Scardina JM, et al. A combinatorial approach to the identification of dipeptide aldehyde inhibitors of beta-amyloid production. J Med Chem 1999; 42: 3889-98.
147. Cordell B, Schirlin D, Peet N (Merrell Dow Pharmaceuticals, Scois Nova Inc.) Preparation of peptide analogs as inhibitors of beta-amyloid protein production. WO 9509838.
148. Nadin A, Sanchez Lopez JM, Neduvelil JG, Thomas SR. A stereocontrolled synthesis of 2R-benzyl-5S-tert-butoxycarbonyl-amino-4R-(tert- butyldimethylsilanyloxy)-6-phenyl-hexanoic acid (Phe-Phe hydroxyethylene dipeptide isostere). Tetrahedron 2001; 57: 1861-4.
149. Dyrks T, Dyrks E, Monning U, Urmoneit B, Turner J, Beyreuther K. Generation of beta A4 from the amyloid protein precursor and fragments thereof. FEBS Lett 1993; 335: 89-93.
150. Nadin A, Owens AP, Castro JL, Harrison T, Shearman MS. Synthesis and gamma-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres. Bioorg Med Chem Lett 2003; 13: 37-41.
151. Felsenstein K, Smith DW, Poss MA, Chaturvedula P, Sloan CP. (Bristol-Myers Squibb Co.) 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives as inhibitors of beta-amyloid protein production. US 5703129.
152. Felsenstein K, Smith DW, Poss MA, Chaturvedula P, Sloan CP. (Bristol-Myers Squibb Company.) Preparation of 5-amino-6-cyclohexyl-4-hydroxyhexanamide derivatives as inhibitors of beta-amyloid protein production for the treatment of Alzheimer's disease. EP 778266.
153. Mori H (Japan). Gamma-secretase inhibitors. WO 2003091278.
154. Tung JS, Guinn AC, Thorsett ED, Pleiss MA (Elan Pharmaceuticals.) Preparation of hydroxyalkanoyl aminopyrazoles and related compounds for inhibiting beta-amyloid peptide release. WO 2003064396.
155. Tung JS, Guinn AC, Thorsett ED, Pleiss MA (Elan Pharmaceuticals.) Preparation of succinoyl aminopyrazoles and related compounds for inhibiting beta-amyloid peptide release. WO 2003094854.
156. Audia JE, Britton TC, Droste JJ, Folmer BK, Huffman GW, Varghese J, et al. (Elan Pharmaceuticals, Eli Lilly & Company.) Preparation of peptides for inhibiting beta-amyloid peptide release and/or its synthesis. US 6207710.
157. Audia JE, Britton TC, Droste JJ, Folmer BK, Huffman GW, Varghese J, et al. (Elan Pharmaceuticals, Eli Lilly & Company.) Preparation of peptides for inhibiting beta-amyloid peptide release and/or its synthesis. US 6191166.
158. Audia JE, Thompson RC, Wilkie SC, Britton TC, Porter WJ, Huffman GW, et al. (Elan Pharmaceuticals, Eli Lilly & Company.) Preparation of cyclic amino acid compounds for inhibiting beta-amyloid peptide release and/or its synthesis. WO 9967220.
159. Audia JE, Porter WJ, Thompson RC, Wilkie SC, Stack DR, Shi Q, et al. (Elan Pharmaceuticals, Eli Lilly & Company.) Preparation of cyclic amino acid compounds for inhibiting beta-amyloid peptide release and/or its synthesis. WO 9967219.
160. Audia JE, Dressman BA, Shi Q. (Elan Pharmaceuticals, Eli Lilly & Company.) Preparation of cyclic amino acid compounds for inhibiting beta-amyloid peptide release and/or its synthesis. WO 9966934.
161. Audia JE, Mabry TE, Nissen JS, Mcdaniel SL (Elan
162. Audia JE, Britton TC, Droste JJ, Folmer BK, Huffman GW, Varghese J, et al. (Athena Neurosciences.) Preparation of N-(phenylacetyl)di- and tripeptide derivatives for inhibiting beta-amyloid peptide release. WO 9822494.
163. Audia JE, Folmer BK, John V, Latimer LH, Nissen JS, Porter WJ, et al. (Athena Neurosciences, Eli Lilly & Co.) Preparation of N-aryl- and N-heteroaryl dipeptides for inhibiting beta-amyloid peptide release. WO 9822493.
164. Audia JE, Folmer BK, John V, Latimer LH, Nissen JS, Reel JK, et al. (Athena Neurosciences.) Preparation of N-aryl- and N-heteroarylamino acid esters for inhibiting beta-amyloid peptide release. WO 9822441.
165. Audia JE, Porter WJ, Scott WL, Stack DR, Thompson RC. (Eli Lilly and Company.) Preparation of beta-amino acid compounds useful for inhibiting beta-amyloid peptide release and/or its synthesis. WO 2001034639.
166. Audia JE, Porter WJ, Scott WL, Stack DR, Thompson RC (Eli Lilly and Company.) Preparation of beta-amino acid compounds useful for inhibiting beta-amyloid peptide release and/or its synthesis. WO 2001034571.
167. Wu J, Tung JS, Nissen JS, Mabry TE, Latimer LH, Eid CN, et al. (Athena Neurosciences, Eli Lilly & Co.) Preparation of N-(aryl/heteroaryl/alkylacetyl) amino acid amides for inhibiting beta-amyloid peptide release and/or its synthesis. WO 9822433.
168. Wu J, Tung JS, Thorsett ED, Reel JK, Porter WJ, Nissen JS, et al. (Elan Pharmaceuticals, Eli Lilly & Company.) Preparation of peptides for inhibiting beta-amyloid peptide release and /or its synthesis. US 6211235.
169. Wu J, Thorsett ED, Nissen JS, Mabry TE, Latimer LH, John V, et al. (Athena Neurosciences, Eli Lilly & Company.) Preparation of N-(aryl/heteroarylacetyl) amino acid esters for use as pharmaceuticals. US 6117901.
170. Wu J, Tung JS, Thorsett ED, Pleiss MA, Nissen JS, Neitz J, et al. (Athena Neurosciences, Eli Lilly & Co.) Preparation of cycloalkyl, lactam, lactone and related compounds for inhibiting beta-amyloid peptide release and/or its synthesis. WO 9828268.
171. Wu J, et al. (Athena Neurosciences, Eli Lilly & Co.) Preparation of N-(aryl/heteroarylacetyl) amino acid esters for inhibiting beta-amyloid peptide release and/or its synthesis. WO 9822430.
172. Dovey HF, John V, Anderson JP, Chen LZ, de Saint AP, Fang LY, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001; 76: 173-81.
173. Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B, et al. The gamma-secretase inhibitor N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 2003; 305: 864-71.
174. Comery TA, Aschmies S, Atchison KP, Borusovic K, Diamantidis G, Gong X, et al. Acute gamma secretase inhibition improves cognition in the Tg2576 mouse model of Alzheimer's diease. Abstract (525.21)- Society for Neuroscience Meeting, New Orleans, November 2003.
175. Wolfe MS, Esler WP, Kimberly WT, Berezovska O, Jack C, Hyman BT. gamma-secretase/presenilin inhibitor causes Notch-deficient phenotype in drosophila. Abstract (244.1)- Society for Neuroscience Meeting, San Diego, November 2001.
176. Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C. A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Reports 2002; 3: 688-94.
177. Lanz TA, Wu H, Landrum CS, Ellerbrock BF, Nye JS, Merchant KM. Reduced A-beta levels in Tg2576 brain, CSF and plasma by potent gamma-secretase inhibitors but not by NSAIDs. Abstract (729.1)- Society for Neuroscience Meeting, New Orleans, November 2003.
178. Lanz TA, Hosley JD, Adams WJ, Merchant KM. Studies of Abeta Pharmacodynamics in the Brain, CSF and Plasma in Young (Plaque-free) Tg2576 Mice Using the -secretase Inhibitor, LY-411575. J Pharmacol Exp Ther 2004; 309(1): 49-55.
179. May PC, Altstiel LD, Bender MH, Boggs LN, Calligaro DO, Fuson KS. Marked reduction in Abeta accumulation and beta amyloid plaque pathology in mice upon chronic treatment with a functional gamma secretase inhibitor. Abstract (687.1)- Society for Neuroscience Meeting, San Diego, November 2001.
180. Audia JE, John V, Latimer L (Eli Lilly and Company, Elan Pharmaceuticals.) Lactam compound preparation for beta-amyloid peptide release inhibition. WO 2002047671.
181. Koenig TM, Mitchell D, Nissen JS (Eli Lilly and Company.) Preparation of lactam derivative useful for inhibiting beta-amyloid peptide release and/or its synthesis. WO 2002040508.
182. Koenig TM, Audia JE, Mitchell D, McDaniel SL, Buccilli LA, Engel GL, Aikins JA (Eli Lilly and Company.) Preparation of lactam derivative useful for inhibiting beta-amyloid peptide release and/or its synthesis. WO 2002040451.
183. Garofalo AW, Wone David WG, Phuc A, Audia JE, Bales CA, Dovey HF, et al. A series of C-terminal amino alcohol dipeptide A beta inhibitors. Bioorg Med Chem Lett 2002; 12: 3051-3.
184. Castro Pineiro JL, Churcher I, Guiblin AR, Harrison T, Kerrad S, Madin A, Nadin AJ, Owens AP, Sparey TJ, Teall MR, Williams S (Merck Sharp & Dohme Limited.) Benzodiazepine derivatives as amyloid precursor protein modulators. WO 2001090084.
185. Churcher I, Nadin AJ, Owens AP (Merck Sharp & Dohme Limited.) Preparation of benzodiazepine derivatives as inhibitors of gamma-secretase. WO 2002030912.
186. Churcher I, Ashton K, Butcher JW, Clarke EE, Harrison T, Lewis HD, et al. A new series of potent benzodiazepine gamma-secretase inhibitors. Bioorg Med Chem Lett 2003; 13: 179-83.
187. Churcher I, Williams S, Kerrad S, Harrison T, Castro JL, Shearman MS, et al. Design and Synthesis of Highly Potent Benzodiazepine gamma-Secretase Inhibitors: Preparation of (2S, 3R)-3-(3, 4-Difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2, 3-dihydro-1H-benzo[e][1, 4]- diazepin-3-yl)butyramide by Use of an Asymmetric Ireland-Claisen Rearrangement. J Med Chem 2003; 46: 2275-8.
188. Owens AP, Nadin A, Talbot AC, Clarke EE, Harrison T, Lewis HD, et al. High affinity, bioavailable 3-Amino-1, 4-benzodiazepine-Based gamma-Secretase inhibitors. Bioorg Med Chem Lett 2003; 13: 4143-5.
189. Nadin A, Sanchez Lopez JM, Owens AP, Howells DM, Talbot AC, Harrison T. New Synthesis of 1, 3-Dihydro-1, 4-benzodiazepin-2(2H)-ones and 3-Amino-1, 3-dihydro-1, 4-benzodiazepin-2(2H)-ones: Pd-Catalyzed Cross-Coupling of Imidoyl Chlorides with Organoboronic Acids. J Org Chem 2003; 68: 2844-52.
190. Olson RE (Du Pont Pharmaceuticals Company.) Succinoylamino benzodiazepines as inhibitors of Aβ protein production. WO 2000038618.
191. Olson RE, Maduskuie TP, Thomas LA (Du Pont Pharmaceuticals Co.) Preparation of succinoylaminoazepinones and related compounds as inhibitors of Abeta-peptide production. WO 2000007995.
192. Zaczek RC, Olson RE, Seiffert DA, Thompson LA (Du Pont Pharmaceuticals Company.) Preparation and use of radioligands to screen inhibitors of beta-amyloid peptide production. WO 2000028331.
193. Rishton GM, Retz DM, Tempest PA, Novotny J, Kahn S, Treanor JJ, et al. Fenchylamine sulfonamide inhibitors of amyloid beta peptide production by the gamma-secretase proteolytic pathway: potential small-molecule therapeutic agents for the treatment of Alzheimer's disease. J Med Chem 2000; 43: 2297-9.
194. Belanger PC, Collins IJ, Hannam JC, Harrison T, Lewis SJ, Madin A, et al. (Merck Sharp & Dohme Limited, Merck Frosst Canada + Co.) Synthesis of sulfonamido-substituted bridged bicycloalkyl derivatives as gamma-secretase inhibitors. WO 2001070677.
195. Collins IJ, Hannam JC, Harrison T, Lewis SJ, Madin A, Sparey TJ, Williams BJ (Merck Sharp & Dohme Limited.) Synthesis of sulfonamido-substituted bridged bicycloalkyl derivatives as gamma-secretase inhibitors. WO 2002036555.
196. Castro Pineiro JL, Hannam JC, Harrison T, Madin A, Ridgill MP (Merck Sharp & Dohme Limited.) Preparation of alkenyl-substituted spirocyclic sulfamides as inhibitors of gamma-secretase. WO 2003093251.
197. Collins IJ, Cooper LC, Harrison T, Keown LE, Madin A, Ridgill MP (Merck Sharp & Dohme Limited.) Preparation of spirocyclic [1, 2, 5]thiadiazole derivatives as gamma-secretase inhibitors for treatment of Alzheimer's disease. WO 2003093252.
198. Campbell A, Ridgill MP (Merck Sharp & Dohme Limited.) Preparation of alkynyl-substituted spirocyclic sulfamides for the treatment of Alzheimer's disease. WO 2003093253.
199. Collins IJ, Cooper LC (Merck Sharp & Dohme Limited.) Preparation of oxadiazole derivatives as gamma-secretase inhibitors for treatment of Alzheimer's disease. WO 2003093264.
200. Hannam JC, Harrison T, Madin A, Sparey TJ (Merck Sharp & Dohme Limited.) Synthesis of sulfonamido-substituted bridged bicycloalkyl derivatives for control of beta-amyloid production. WO 2003013506.
201. Kreft AF, Cole DC, Woller KR, Stock JR, Kutterer KM, Kubrak DM, et al. (Wyeth, Arqule.) Preparation of substituted phenylsulfonamide derivatives as inhibitors of beta amyloid production. WO 2003103660.
202. Kreft AF, Cole DC, Wolter KR, Stock JR, Diamanitis G, Kurbrak DM, et al. (Wyeth, Arqule.) Preparation of N-substituted thiophene- and furansulfonamides as inhibitors of beta-amyloid production. WO 2002057252.
203. Tian G, Ghanekar SV, Aharony D, Shenvi AB, Jacobs RT, Liu X, et al. The mechanism of gamma -secretase. Multiple inhibitor binding sites for transition state analogs and small molecule inhibitors. J Biol Chem 2003; 278: 28968-75.
204. Smith DW, Munoz B, Srinivasan K, Bergstrom CP, Chaturvedula PV, Deshpande MS, et al. (Merck & Co., Bristol-Myers Squibb Company.) Preparation of sulfonamide derivs. as amyloid beta production inhibitors useful in treating or preventing diseases related to Abeta. WO 2000050391.
205. Parker MF, McElhone KE, Mate RA, Bronson JJ, Gai Y, Bergstrom CP, et al. (Bristol-Myers Squibb Company.) Preparation of α-(N-sulfonamido)acetamides as beta-amyloid inhibitors. WO 2003053912.
206. Josien HB, Clader JW, Asberom T, Pissarnitski DA (Schering Corporation.) Preparation of piperidinylsulfonamides as gamma-secretase inhibitors. WO 2003013527.
207. Asberom T, Guzik HS, Josien HB, Pissarnitski DA. (Schering Corporation.) Preparation of 1-sulfonyl quinoline derivatives as gamma-secretase inhibitors. WO 2003014075.
208. Pissarnitski DA, Josien HB, Smith EM, Clader JW, Asberom T, Guo T, et al. (Schering Corporation, Pharmacopeia.) Preparation of 1-(arylsulfonyl)piperidines as gamma-secretase inhibitors for treatment of neurodegenerative diseases. WO 2003066592.
209. Brands KMJ, Davies AJ, Oakley PJ, Scott JP, Shaw DE, Teall MR (Merck Sharp & Dohme Limited, Merck & Co.) Synthesis of cyclohexanone derivatives. WO 2004013090.
210. Castro Pineiro JL, Churcher I, Dinnell K, Harrison T, Kerrad S, Nadin AJ, et al. (Merck Sharp & Dohme Limited.) Preparation of aryl sulfones which modulate the action of gamma secretase. WO 2002081435.
211. Churcher I, Dinnell K, Harrison T, Kerrad S, Nadin AJ, Oakley PJ, et al. (Merck Sharp & Dohme Limited.) Preparation of 1-phenyl-1-(arylsulfonyl)cyclo-hexanes for treatment of Alzheimer's disease. WO 2003018543.
212. Harrison T, Oakley PJ, Teall MR. (Merck Sharp & Dohme Limited.) Preparation of arylsulfones as modulators of gamma secretase. WO 2002081433.
213. Hendrix M, Baumann K, Grosser R, Koenig G, Duesterhus V, Krueger J. (Bayer Aktiengesellschaft.) Preparation of benzylsulfonylbenzenes and related compounds as gamma-secretase inhibitors for the treatment of Alzheimer's disease. WO 2003059335.
214. Yasukochi T, Ito M, Kubota H, Miyauchi S, Saito M. (Daiichi Pharmaceutical Co.) Preparation of benzyl or heterocyclylmethyl phenyl or heterocyclyl sulfones as beta-amyloid protein production/secretion inhibitors. WO 2003055850.
215. Himmelsbach F, Fuchs K, Briem H, Fechteler K, Kostka M, Dorner-Ciossek C, et al. (Boehringer Ingelheim Pharma K.-G.) Preparation of diaminopyrimidines as inhibitors of beta amyloid formation or its release. WO 2003032994.
216. Bihel F, Delaage M, Jouve C, Kraus J-L, Pourquie O, Williamson T-L, et al. (Trophos.) Isocoumarin derivatives, particularly 7-amino-4-chloro-3-(2-methoxyethoxy)isochromen-1-ones, inhibiting production of amyloid peptide, preparation, compositions containing them, and uses. WO 2002048102.
217. Petit A, Bihel F, Alves dC, Pourquie O, Checler F, Kraus JL. New protease inhibitors prevent gamma-secretase-mediated production of Abeta40/42 without affecting Notch cleavage. Nat Cell Biol 2001; 3: 507-11.
218. Petit A, Pasini A, Alves da Costa C, Ayral E, Hernandez JF, Dumanchin-Njock C, et al. JLK isocoumarin inhibitors: Selective gamma-secretase inhibitors that do not interfere with notch pathway in vitro or in vivo. J Neurosci Res 2003; 74: 370-7.
219. Esler WP, Das C, Campbell WA, Kimberly WT, Kornilova AY, Diehl TS, et al. Amyloid-lowering isocoumarins are not direct inhibitors of gamma-secretase. Nat Cell Biol 2002; 4: E110-E111.
220. Hadland BK, Manley NR, Su D, Longmore GD, Moore CL, Wolfe MS, et al. Gamma -secretase inhibitors repress thymocyte development. Proc Natl Acad Sci USA 2001; 98: 7487-91.
221. Doerfler P, Shearman MS, Perlmutter RM. Presenilin-dependent gamma-secretase activity modulates thymocyte development. Proc Natl Acad Sci USA 2001; 98: 9312-7.
222. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 2003; 278: 46107-16.
223. Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, et al. Control of endodermal endocrine development by Hes-1. Nat Genet 2000; 24: 36-44.
224. McKenzie GJ, Young LL, Briend E, Lamb JR, Dallman MJ, Champion BR. Notch signalling in the regulation of peripheral T-cell function. Semin Cell Dev Biol 2003; 14: 127-34.
225. Costa RM, Honjo T, Silva AJ. Learning and Memory Deficits in Notch Mutant Mice. Curr Biol 2003; 13: 1348-54.
226. Presente A, Boyles RS, Serway CN, De Belle JS, Andres AJ. Notch is required for long-term memory in Drosophila. Proc Natl Acad Sci USA 2004; 101: 1764-8.
227. Conboy IM, Conboy MJ, Smythe GM, Rando A. Notch-Mediated Restoration of Regenerative Potential to Aged Muscle. Science (Washington, DC, United States) 2003; 302: 1575-8.
228. In't Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001; 345: 1515-21.
229. In t'Veld BA, Launer LJ, Breteler MM, Hofman A, Stricker BH. Pharmacologic agents associated with a preventive effect on Alzheimer's disease: a review of the epidemiologic evidence. Epidemiol Rev 2002; 24: 248-68.
230. Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997; 48: 626-32.
231. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414: 212-6.
232. Sagi SA, Weggen S, Eriksen J, Golde TE, Koo EH. The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of kappa B kinase, and NF kappa B, do not reduce amyloid beta 42 production. J Biol Chem 2003; 278: 31825-30.
233. Takahashi Y, Hayashi I, Tominari Y, Rikimaru K, Morohashi Y, Kan T, et al. Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J Biol Chem 2003; 278: 18664-70.
234. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003; 112: 440-9.
235. Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V, Fauq A, et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem 2003; 278: 31831-7.
236. Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Golde TE, Koo EH. Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain. J Biol Chem 2003; 278: 30748-54.
237. Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science 2003; 302: 1215-7.
238. Frolich L, Fox J, Padberg F, Maurer K, Moller HJ, Hampel H. Targets of antidementive therapy: drugs with a specific pharmacological mechanism of action. Curr Pharm Design 2004; 10(3): 223-9.
239. Gsell W, Jungkunz G, Riederer P. Functional neurochemistry of Alzheimer's disease. Curr Pharm Design 2004; 10(3): 265-93.
240. Ibach B, Haen E. Acetylcholinesterase inhibition in Alzheimer's Disease. Curr Pharm Design 2004; 10(3): 231-51.