γ-Secretase Modulators: Current status and future directions

Progress in Medicinal Chemistry

Volumn 53, Issue , 2014, Pages 101-145

  Hall, Adrian ^a   Patel, Toshal R ^a  

^a EISAI CO LTD   (Japan)

Author keywords

Alzheimer's disease; Secretase; Secretase inhibitors; Secretase modulators

Indexed keywords

ACID DERIVATIVE; GAMMA SECRETASE; IMIDAZOLE DERIVATIVE; NATURAL PRODUCT; PROTEIN DERIVATIVE; UNCLASSIFIED DRUG; SECRETASE;

ALZHEIMER DISEASE; ARTICLE; BIOLOGY; CLINICAL STUDY; DRUG CLASSIFICATION; DRUG MANUFACTURE; PRIORITY JOURNAL; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; HUMAN; PHYSIOLOGY;

ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; HUMANS; IMIDAZOLES;

EID: 84892422681     PISSN: 00796468     EISSN: 18757863     Source Type: Book Series    
DOI: 10.1016/B978-0-444-63380-4.00003-2     Document Type: Chapter

References (97)

1. W. Thies, and L. Bleiler 2013 Alzheimer's disease facts and figures Alzheimers Dement 9 2 2013 208 245
2. R.E. Tanzi The genetics of Alzheimer disease Cold Spring Harb Perspect Med 2 10 2012 a006296
3. D.J. Selkoe, and M.S. Wolfe Presenilin: running with scissors in the membrane Cell 131 2 2007 215 221
4. P. Osenkowski, W. Ye, R. Wang, M.S. Wolfe, and D.J. Selkoe Direct and potent regulation of gamma-secretase by its lipid microenvironment J Biol Chem 283 33 2008 22529 22540
5. P. Osenkowski, H. Li, W. Ye, D. Li, L. Aeschbach, and P.C. Fraering et al. Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution J Mol Biol 385 2 2009 642 652
6. T. Jonsson, J.K. Atwal, S. Steinberg, J. Snaedal, P.V. Jonsson, and S. Bjornsson et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline Nature 488 7409 2012 96 99
7. D. Oehlrich, D.J. Berthelot, and H.J. Gijsen Gamma-secretase modulators as potential disease modifying anti-Alzheimer's drugs J Med Chem 54 3 2011 669 698
8. C.R. Hopkins ACS chemical neuroscience molecule spotlight on BMS-708163 ACS Chem Neurosci 3 3 2012 149 150
9. C.R. Hopkins ACS chemical neuroscience molecule spotlight on ELND006: another gamma-secretase inhibitor fails in the clinic ACS Chem Neurosci 2 6 2011 279 280
10. R.S. Doody, R. Raman, M. Farlow, T. Iwatsubo, B. Vellas, and S. Joffe et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease N Engl J Med 369 4 2013 341 350
11. C.R. Hopkins ACS chemical neuroscience molecule spotlight on Begacestat (GSI-953) ACS Chem Neurosci 3 1 2012 3 4
12. K. Mullane, and M. Williams Alzheimer's therapeutics: continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond? Biochem Pharmacol 85 3 2013 289 305
13. M. Pettersson, G.W. Kauffman, C.W. am Ende, N.C. Patel, C. Stiff, and T.P. Tran et al. Novel gamma-secretase modulators: a review of patents from 2008 to 2010 Expert Opin Ther Pat 21 2 2011 205 226
14. M. Pettersson, A.F. Stepan, G.W. Kauffman, and D.S. Johnson Novel gamma-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012 Expert Opin Ther Pat 23 2013 1349 1366
15. B. Bulic, J. Ness, S. Hahn, A. Rennhack, T. Jumpertz, and S. Weggen Chemical biology, molecular mechanism and clinical perspective of gamma-secretase modulators in Alzheimer's disease Curr Neuropharmacol 9 4 2011 598 622
16. M.T. Heneka, M.P. Kummer, S. Weggen, B. Bulic, G. Multhaup, and L. Munter et al. Molecular mechanisms and therapeutic application of NSAIDs and derived compounds in Alzheimer's disease Curr Alzheimer Res 8 2 2011 115 131
17. R. Pignatello, V. Panto, S. Salmaso, S. Bersani, V. Pistara, and V. Kepe et al. Flurbiprofen derivatives in Alzheimer's disease: synthesis, pharmacokinetic and biological assessment of lipoamino acid prodrugs Bioconjug Chem 19 1 2008 349 357
18. S. Sivilia, L. Lorenzini, A. Giuliani, M. Gusciglio, M. Fernandez, and V.A. Baldassarro et al. Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice BMC Neurosci 14 2013 44
19. B.B. Van, J.M. Chen, G. Treton, M. Desmidt, C. Hopf, and N. Ramsden et al. Chronic treatment with a novel gamma-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer's disease Br J Pharmacol 163 2 2011 375 389
20. H.J. Gijsen, and M. Mercken Gamma-secretase modulators: can we combine potency with safety? Int J Alzheimers Dis 2012 2012 295207 10.1155/2012/295207 Epub@2012 Dec 17
21. K. Rogers, K.M. Felsenstein, L. Hrdlicka, Z. Tu, F. Albayya, and W. Lee et al. Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice Mol Neurodegener 7 2012 61
22. Blurton P, Burkamp F, Churcher I, Harrison T, Neduvelil J, inventors. Arylacetic acids and related compounds and their preparation, pharmaceutical compositions and their use for treatment of diseases associated with the deposition of β-amyloid peptides in the brain such as Alzheimer's disease. Patent WO2006008558A1; 2006.
23. A. Hall, R.L. Elliott, G.M. Giblin, I. Hussain, J. Musgrave, and A. Naylor et al. Piperidine-derived gamma-secretase modulators Bioorg Med Chem Lett 20 3 2010 1306 1311
24. J. Hawkins, D.C. Harrison, S. Ahmed, R.P. Davis, T. Chapman, and I. Marshall et al. Dynamics of Abeta42 reduction in plasma, CSF and brain of rats treated with the gamma-secretase modulator, GSM-10h Neurodegener Dis 8 6 2011 455 464
25. I. Hussain, D.C. Harrison, J. Hawkins, T. Chapman, I. Marshall, and L. Facci et al. TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to gamma-secretase modulation and amyloid-beta(4)(2) lowering by GSM-10 h Neurodegener Dis 8 1-2 2011 15 24
26. M.G. Stanton, J. Hubbs, D. Sloman, C. Hamblett, P. Andrade, and M. Angagaw et al. Fluorinated piperidine acetic acids as gamma-secretase modulators Bioorg Med Chem Lett 20 2 2010 755 758
27. 3-secretase modulator ACS Med Chem Lett 2 10 2011 786 791
28. Z. Xin, H. Peng, A. Zhang, T. Talreja, G. Kumaravel, and L. Xu et al. Discovery of 4-aminomethylphenylacetic acids as gamma-secretase modulators via a scaffold design approach Bioorg Med Chem Lett 21 24 2011 7277 7280
29. Am E, Fish BA, Johnson DS, Lira R, O'Donnell CJ, Pettersson MY, et al., inventors. Aminocyclohexanes and aminotetrahydropyrans as γ-secretase modulators and their preparation and use for the treatment of neurological and psychiatric diseases. Patent WO2011092611A1; 2011.
30. Yamasaki S, Honjo E, Samizu K, Kuroda A, Yonezawa K, Hayashibe S, et al., inventors. Preparation of cycloalkane compounds as γ secretase modulators. Patent WO2012046771A1; 2012.
31. Kimura T, Kawano K, Doi E, Kitazawa N, Shin K, Miyagawa T, et al., inventors. Preparation of cinnamide, 3-benzylidenepiperidin-2-one, phenylpropynamide compounds as amyloid β production inhibitors. Patent WO2005115990A1; 2005.
32. U. Yngve, K. Paulsen, I. Macsari, M. Sundstrom, E. Santangelo, and C. Linde et al. Triazolopyrimidinones as [gamma]-secretase modulators: structure-activity relationship, modulator profile, and in vivo profiling Med Chem Commun 4 2 2013 422 431
33. E. Portelius, B.B. Van, U. Andreasson, M.K. Gustavsson, M. Mercken, and H. Zetterberg et al. Acute effect on the Abeta isoform pattern in CSF in response to gamma-secretase modulator and inhibitor treatment in dogs J Alzheimers Dis 21 3 2010 1005 1012
34. M.Z. Kounnas, A.M. Danks, S. Cheng, C. Tyree, E. Ackerman, and X. Zhang et al. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease Neuron 67 5 2010 769 780
35. Z. Wan, A. Hall, Y. Jin, J.N. Xiang, E. Yang, and A. Eatherton et al. Pyridazine-derived gamma-secretase modulators Bioorg Med Chem Lett 21 13 2011 4016 4019
36. Eatherton AJ, Giblin GMP, Hall A, Johnson MR, Le J, Mitchell WL, et al., inventors. Pyridazine derivatives for inhibiting β-amyloid peptide production and their preparation, pharmaceutical compositions and use in the treatment of Alzheimer's disease. Patent WO2009050227A1; 2009.
37. Z. Wan, A. Hall, Y. Sang, J.N. Xiang, E. Yang, and B. Smith et al. Pyridine-derived gamma-secretase modulators Bioorg Med Chem Lett 21 16 2011 4832 4835
38. Y. Huang, T. Li, A. Eatherton, W.L. Mitchell, N. Rong, and L. Ye et al. Orally bioavailable and brain-penetrant pyridazine and pyridine-derived gamma-secretase modulators reduced amyloidogenic Abeta peptides in vivo Neuropharmacology 70 2013 278 286 10.1016/j.neuropharm.2013.02.003 Epub@2013 Feb 26
39. T. Lubbers, A. Flohr, S. Jolidon, P. David-Pierson, H. Jacobsen, and L. Ozmen et al. Aminothiazoles as gamma-secretase modulators Bioorg Med Chem Lett 21 21 2011 6554 6558
40. F. Bischoff, D. Berthelot, C.M. De, G. Macdonald, G. Minne, and D. Oehlrich et al. Design and synthesis of a novel series of bicyclic heterocycles as potent gamma-secretase modulators J Med Chem 55 21 2012 9089 9106
41. H. Borghys, M. Tuefferd, B. Van, E. Clessens, L. Dillen, and W. Cools et al. A canine model to evaluate efficacy and safety of + -secretase inhibitors and modulators J Alzheimers Dis 28 4 2012 809 822
42. D. Oehlrich, F.J. Rombouts, D. Berthelot, F.P. Bischoff, M.A. De Cleyn, and L. Jaroskova et al. Design and synthesis of bicyclic heterocycles as potent gamma-secretase modulators Bioorg Med Chem Lett 23 17 2013 4794 4800
43. Cuss F. BMS-Cowen Healthcare Conference March 2013. 3-3-2013.
44. Marcin LR, Thompson LA, III, Boy KM, Guernon JM, Higgins MA, Shi J, et al., inventors. Preparation of bicyclic compounds, especially bicyclic triazoles, for the reduction of beta-amyloid protein production. Patent WO2010083141A1; 2010.
45. Boy KM, Guernon JM, Macor JE, Olson RE, Shi J, Thompson LA, III, et al., inventors. Preparation of fused pyrimidine compounds as modulators of β-amyloid production. Patent WO2011014535A1; 2011.
46. Boy KM, Guernon JM, Macor JE, Olson RE, Shi J, Thompson LA, III, et al., inventors. Preparation of bicyclic pyrimidine compounds for the reduction of β-amyloid production. Patent WO2012103297A1; 2012.
47. Boy KM, Guernon JM, Macor JE, Thompson LA, III, Wu YJ, Zhang Y, inventors. Preparation of macrocyclic compounds fused to benzene and pyrimidine rings for the reduction of beta-amyloid production. Patent WO2012009309A1; 2012.
48. Allen MP, Am E, Brodney MA, Dounay AB, Johnson DS, Pettersson MY, et al., inventors. Preparation of phenylimidazole derivatives and analogs for use as gamma-secretase modulators. Patent WO2010100606A1; 2010.
49. Am E, Johnson DS, O'Donnell CJ, Pettersson MY, Subramanyam C, inventors. Preparation of heteroaryl imidazoles and heteroaryl triazoles as γ-secretase modulators. Patent WO2011048525A1; 2011.
50. M. Pettersson, D.S. Johnson, C. Subramanyam, K.R. Bales, C.W. am Ende, and B.A. Fish et al. Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active gamma-secretase modulators Bioorg Med Chem Lett 22 8 2012 2906 2911
51. Am E, Fish BA, Green ME, Johnson DS, Mullins PB, O'Donnell CJ, et al., inventors. Preparation of pyrido[1,2-a]pyrazine-1,6-dione derivatives as γ-secretase modulators. Patent WO2012131539A1; 2012.
52. A. Rivkin, S.P. Ahearn, S.M. Chichetti, Y.R. Kim, C. Li, and A. Rosenau et al. Piperazinyl pyrimidine derivatives as potent gamma-secretase modulators Bioorg Med Chem Lett 20 3 2010 1269 1271
53. A. Rivkin, S.P. Ahearn, S.M. Chichetti, C.L. Hamblett, Y. Garcia, and M. Martinez et al. Purine derivatives as potent gamma-secretase modulators Bioorg Med Chem Lett 20 7 2010 2279 2282
54. C. Fischer, S. Shah, B.L. Hughes, G.N. Nikov, J.L. Crispino, and R.E. Middleton et al. Quinazolinones as gamma-secretase modulators Bioorg Med Chem Lett 21 2 2011 773 776
55. C. Fischer, S.L. Zultanski, H. Zhou, J.L. Methot, W.C. Brown, and D.M. Mampreian et al. Triazoles as gamma-secretase modulators Bioorg Med Chem Lett 21 13 2011 4083 4087
56. C. Fischer, S.L. Zultanski, H. Zhou, J.L. Methot, S. Shah, and H. Nuthall et al. Triazoloamides as potent gamma-secretase modulators with reduced hERG liability Bioorg Med Chem Lett 22 9 2012 3140 3146
57. J.P. Caldwell, C.E. Bennett, T.M. McCracken, R.D. Mazzola, T. Bara, and A. Buevich et al. Iminoheterocycles as gamma-secretase modulators Bioorg Med Chem Lett 20 18 2010 5380 5384
58. 3- secretase modulators ACS Med Chem Lett 1 4 2010 184 187
59. J. Qin, P. Dhondi, X. Huang, M. Mandal, Z. Zhao, and D. Pissarnitski et al. Discovery of fused 5,6-bicyclic heterocycles as gamma-secretase modulators Bioorg Med Chem Lett 21 2 2011 664 669
60. 3-secretase modulators ACS Med Chem Lett 2 6 2011 471 476
61. Gerlach K, Heine N, Hobson S, Hoenke C, Weber A, inventors. Preparation of dihydrothienopyrimidines γ-secretase modulators. Patent WO2013020992A1; 2013.
62. Nishitomi K, Kano K, Kato I, Sako Y, inventors. Preparation of pharmaceutical products containing heterocyclic sulfonamide compounds as γ-secretase modulators. Patent WO2010126002A1; 2010.
63. Kato I, Kano K, inventors. Preparation of lactam or benzenesulfonamide compounds as inhibitors for production of amyloid β protein. Patent WO2011007819A1; 2011.
64. Iwama S, Nakagawa H, Kato Y, inventors. Oxadiazole derivative as therapeutic agent for β-amyloid-associated neuropsychiatric disorders. Patent WO2011001931A1; 2011.
65. Iwama S, Kato Y, Kobayashi T, Fusano A, inventors. Preparation of 4-(1H-imidazol-1-y)benzamide and (1H-imidazol-1-y)pyridinecarboxamide derivatives as beta amyloid 42 production inhibitors. Patent WO2011059048A1; 2011.
66. Iwama S, Ikeda T, Kobayashi T, inventors. Preparation of 4-(4-pyridinyl)phenyl-substituted fused 1,2,4-triazole derivatives as inhibitors of beta-amyloid production. Patent WO2012057300A1; 2012.
67. H.J.M. Gijsen, and M. Mercken γ-Secretase modulators: can we combine potency with safety? Int J Alzheimers Dis 2012 2012 Article ID 295207
68. H.J.M. Gijsen, and F.P. Bischoff Secretase inhibitors and modulators as a disease-modifying approach against Alzheimer's disease Annu Rep Med Chem 47 2012 55 69
69. M.A. Findeis, F. Schroeder, T.D. McKee, D. Yager, P.C. Fraering, and S.P. Creaser et al. Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of Actaea racemosa ACS Chem Neurosci 3 11 2012 941 951
70. W.F. Austin, J.L. Hubbs, N.O. Fuller, S.P. Creaser, T.D. McKee, and R.M.B. Loureiro et al. SAR investigations on a novel class of gamma-secretase modulators based on a unique scaffold Med Chem Commun 4 3 2013 569 574
71. N.O. Fuller, J.L. Hubbs, W.F. Austin, S.P. Creaser, T.D. McKee, and R.M.B. Loureiro et al. Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside ACS Med Chem Lett 3 11 2012 908 913
72. J.L. Hubbs, N.O. Fuller, W.F. Austin, R. Shen, S.P. Creaser, and T.D. McKee et al. Optimization of a natural product-based class of γ-secretase modulators J Med Chem 55 21 2012 9270 9282
73. B. Tate, T.D. McKee, R.M. Loureiro, J.A. Dumin, W. Xia, and K. Pojasek et al. Modulation of gamma-secretase for the treatment of Alzheimer's disease Int J Alzheimers Dis 2012 2012 210756 10.1155/2012/210756 Epub@2012 Dec@19
74. R.M. Loureiro, J.A. Dumin, T.D. McKee, W.F. Austin, N.O. Fuller, and J.L. Hubbs et al. Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models Alzheimers Res Ther 5 2 2013 19
75. L. Di, J.P. Umland, G. Chang, Y. Huang, Z. Lin, and D.O. Scott et al. Species independence in brain tissue binding using brain homogenates Drug Metab Dispos 39 7 2011 1270 1277
76. X. Li, S. Dang, C. Yan, X. Gong, J. Wang, and Y. Shi Structure of a presenilin family intramembrane aspartate protease Nature 493 7430 2013 56 61
77. 3-secretase modulators directly bind to presenilin-1 ACS Chem Neurosci 2 12 2011 705 710
78. S. Weggen, and D. Beher Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease Alzheimers Res Ther 4 2 2012 9
79. T. Jumpertz, A. Rennhack, J. Ness, S. Baches, C.U. Pietrzik, and B. Bulic et al. Presenilin is the molecular target of acidic gamma-secretase modulators in living cells PLoS One 7 1 2012 e30484
80. Y. Ohki, T. Higo, K. Uemura, N. Shimada, S. Osawa, and O. Berezovska et al. Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1 EMBO J 30 23 2011 4815 4824
81. A. Ebke, T. Luebbers, A. Fukumori, K. Shirotani, C. Haass, and K. Baumann et al. Novel gamma-secretase enzyme modulators directly target presenilin protein J Biol Chem 286 43 2011 37181 37186
82. N. Pozdnyakov, H.E. Murrey, C.J. Crump, M. Pettersson, T.E. Ballard, and C.W. am Ende et al. Gamma-secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin J Biol Chem 288 14 2013 9710 9720
83. T. Tomita, and T. Iwatsubo Structural biology of presenilins and signal peptide peptidases J Biol Chem 288 2013 14673 14680
84. R.C. Green, L.S. Schneider, D.A. Amato, A.P. Beelen, G. Wilcock, and E.A. Swabb et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial JAMA 302 23 2009 2557 2564
85. R. Narlawar, B.I. Perez Revuelta, C. Haass, H. Steiner, B. Schmidt, and K. Baumann Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators J Med Chem 49 26 2006 7588 7591
86. G.K. Wilcock, S.E. Black, S.B. Hendrix, K.H. Zavitz, E.A. Swabb, and M.A. Laughlin Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial Lancet Neurol 7 6 2008 483 493
87. D.R. Galasko, N. Graff-Radford, S. May, S. Hendrix, B.A. Cottrell, and S.A. Sagi et al. Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals Alzheimer Dis Assoc Disord 21 4 2007 292 299
88. J.L. Eriksen, S.A. Sagi, T.E. Smith, S. Weggen, P. Das, and D.C. McLendon et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo J Clin Invest 112 3 2003 440 449
89. B.P. Imbimbo, G.E. Del, D. Colavito, A. D'Arrigo, C.M. Dalle, and G. Villetti et al. 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)- cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity J Pharmacol Exp Ther 323 3 2007 822 830
90. J. Ross, S. Sharma, J. Winston, M. Nunez, G. Bottini, and M. Franceschi et al. CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study Curr Alzheimer Res 10 7 2013 742 753
91. CereSpir Announcement. http://www.cerespir.com/072613b.htm. 1-8-2013.
92. En Vivo EVP0962 Press release, http://www.envivopharma.com/news-item.php? id=44; 2013.
93. T. Hashimoto, A. Ishibashi, H. Hagiwara, Y. Murata, O. Takenaka, and T. Miyagawa E2012: a novel gamma-secretase modulator-pharmacology part Alzheimers Dement 6 4 2010 S242
94. H. Amino, H. Hagiwara, Y. Murata, H. Watanabe, T. Sasaki, and T. Miyagawa E2012: a novel gamma-secretase modulator-mechanism of action Alzheimer's Dement 6 4 2010 S541 S542
95. C. Nagy, E. Schuck, A. Ishibashi, Y. Nakatani, B. Rege, and V. Logovinsky E2012, a novel gamma-secretase modulator, decreases plasma amyloid-beta (A+) levels in humans Alzheimer's Dement 6 4 2010 S574
96. Eisai Financial Update 1st May 2013. http://www.eisai.com/pdf/eir/emat/ e4523-130513.pdf; 1-5-2013.
97. E2212 clinical trials. http://clinicaltrials.gov/ct2/show/NCT01221259? intr=E2212&rank=1; 2013.