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International Journal of Alzheimer’s Disease
Volume 2012 (2012), Article ID 210756, 10 pages
http://dx.doi.org/10.1155/2012/210756
Research Article

Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease

Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA

Received 13 August 2012; Accepted 8 November 2012

Academic Editor: Jeremy Toyn

Copyright © 2012 Barbara Tate et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. N. Kakuda, S. Funamoto, S. Yagishita et al., “Equimolar production of amyloid β-protein and amyloid precursor protein intracellular domain from β-carboxyl-terminal fragment by γ-secretase,” Journal of Biological Chemistry, vol. 281, no. 21, pp. 14776–14786, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. T. Sato, N. Dohmae, Y. Qi et al., “Potential link between amyloid β-protein 42 and C-terminal fragment γ 49-99 of β-amyloid precursor protein,” Journal of Biological Chemistry, vol. 278, no. 27, pp. 24294–20301, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. Y. Qi-Takahara, M. Morishima-Kawashima, Y. Tanimura et al., “Longer forms of amyloid β protein: implications for the mechanism of intramembrane cleavage by γ-secretase,” Journal of Neuroscience, vol. 25, no. 2, pp. 436–445, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Takami, Y. Nagashima, Y. Sano et al., “γ-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of β-carboxyl terminal fragment,” Journal of Neuroscience, vol. 29, no. 41, pp. 13042–13052, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. T. E. Golde, Y. Ran, and K. M. Felsenstein, “Shifting a complex debate on γ-secretase cleavage and Alzheimer's disease,” The EMBO Journal, vol. 31, no. 10, pp. 2237–2239, 2012. View at Publisher · View at Google Scholar
  6. N. Suzuki, T. T. Cheung, X. D. Cai et al., “An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants,” Science, vol. 264, no. 5163, pp. 1336–1340, 1994. View at Scopus
  7. T. Saito, T. Suemoto, N. Brouwers et al., “Potent amyloidogenicity and pathogenicity of Aβ 243,” Nature Neuroscience, vol. 14, no. 8, pp. 1023–1032, 2011. View at Publisher · View at Google Scholar
  8. J. T. Jarrett, E. P. Berger, and P. T. Lansbury Jr., “The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease,” Biochemistry, vol. 32, no. 18, pp. 4693–4697, 1993. View at Scopus
  9. J. Milano, J. McKay, C. Dagenais et al., “Modulation of Notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation,” Toxicological Sciences, vol. 82, no. 1, pp. 341–358, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. G. H. Searfoss, W. H. Jordan, D. O. Calligaro et al., “Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor,” Journal of Biological Chemistry, vol. 278, no. 46, pp. 46107–46116, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. G. T. Wong, D. Manfra, F. M. Poulet et al., “Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits γ-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation,” Journal of Biological Chemistry, vol. 279, no. 13, pp. 12876–12882, 2004. View at Publisher · View at Google Scholar · View at Scopus
  12. E. Lilly, “Lilly Halts Development of Semagacestat for Alzheimer's Disease Based on Preliminary Results of Phase III Clinical Trials,” 2010, http://newsroom.lilly.com/releasedetail.cfm?releaseid=499794.
  13. D. J. Selkoe, “Resolving controversies on the path to Alzheimer's therapeutics,” Nature Medicine, vol. 17, no. 9, pp. 1060–1065, 2011.
  14. B. P. Imbimbo, F. Panza, V. Frisardi et al., “Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: still a viable option?” Expert Opinion on Investigational Drugs, vol. 20, no. 3, pp. 325–341, 2011. View at Publisher · View at Google Scholar · View at Scopus
  15. S. Weggen, J. L. Eriksen, P. Das et al., “A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity,” Nature, vol. 414, no. 6860, pp. 212–216, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. T. E. Golde, L. S. Schneider, and E. H. Koo, “Anti-Aβ therapeutics in alzheimer's disease: the need for a paradigm shift,” Neuron, vol. 69, no. 2, pp. 203–213, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. B. P. Imbimbo, “Why did tarenflurbil fail in alzheimer's disease?” Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 757–760, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. R. C. Green, L. S. Schneider, D. A. Amato et al., “Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial,” Journal of the American Medical Association, vol. 302, no. 23, pp. 2557–2564, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. B. Bulic, J. Ness, S. Hahn, A. Rennhack, T. Jumpertz, and S. Weggen, “Chemical biology, molecular mechanism and clinical perspective of γ-secretase modulators in Alzheimer's disease,” Current Neuropharmacology, vol. 9, no. 4, pp. 598–622, 2011.
  20. J. L. Hubbs, N. O. Fuller, W. F. Austin et al., “Optimization of a natural product-based class of gamma-secretase modulators,” Journal of Medicinal Chemistry, vol. 55, no. 21, pp. 9270–9282, 2012. View at Publisher · View at Google Scholar
  21. E. H. M. Koo, T. E. Golde, and D. R. Galasko, “Nonsteroidal antiinflammatory drug (NSAID) and NSAID derivative amyloid Aβ42 polypeptide-lowering agents for the treatment of Alzheimer's disease, and screening methods,” pp. 73, Mayo Foundation for Medical Education and Research, USA, 2001.
  22. L. Raveglia, I. Peretto, S. Radaelli, B. P. Imbimbo, A. Rizzi, and G. Villetti, “Preparation of 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases,” pp. 91, Chiesi Farmaceutici S.p.A., Italy, 2004.
  23. P. Blurton, et al., “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,” pp. 58, Merck Sharp & Dohme Limited, UK, 2006.
  24. C. Y. Ho, Preparation of Biphenyl Derivatives as γ-secretAse Modulators, Janssen Pharmaceutica, Belg, Germany, 2009.
  25. F. Wilson, A. Reid, V. Reader, et al., “Preparation of biphenylacetic acids as γ-secretase modulators for the treatment of Alzheimer's disease,” pp. 57, Cellzome, Germany, 2006.
  26. G. Shapiro and R. Chesworth, “1,3,4-Trisubstituted benzenes as γ-secretase inhibitors and their preparation and use in the treatment of neurodegenerative diseases,” pp. 165, Envivo Pharmaceuticals, USA, 2009.
  27. J. J. Kulagowski, A. Madin, P. M. Ridgill, and M. E. Seward, “Preparation of piperidines and related compounds for treatment of Alzheimer's disease,” pp. 178, Merck Sharp & Dohme Limited, UK, 2006.
  28. A. Hall, R. L. Elliott, G. M. P. Giblin et al., “Piperidine-derived γ-secretase modulators,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 3, pp. 1306–1311, 2010. View at Publisher · View at Google Scholar
  29. E. C. W. Am, et al., “Aminocyclohexanes and aminotetrahydropyrans as γ-secretase modulators and their preparation and use for thetreatment of neurological and psychiatric diseases,” pp. 91, Pfizer, USA, 2011.
  30. S. Cheng, D. D. Comer, L. Mao, G. P. Balow, and D. Pleynet, “Aryl compounds and uses in modulating amyloid β,” pp. 178, Neurogenetics, USA 2004.
  31. K. Baumann, et al., “Preparation of thiazolyl-substituted imidazolylphenylamine derivatives and related compounds as modulators of amyloid beta,” pp. 32, Hoffmann-La Roche, USA, 2008.
  32. L. R. Marcin, et al., “Preparation of bicyclic compounds, especially bicyclic triazoles, for the reduction of beta-amyloid protein production,” pp. 242, Bristol-Myers Squibb Company, USA, 2010.
  33. R. Forsblom, K. Paulsen, M. Waldman, D. Rotticci, and E. Santangelo, “Preparation of 2-aminopyrimidines as amyloid beta modulators,” pp. 227, AstraZeneca AB, Sweden, 2010.
  34. K. Biswas, J. J. Chen, J. R. Falsey, et al., “Preparation of urea compounds as gamma secretase modulators,” pp. 116, Amgen, USA, 2009.
  35. H. J. M. Gijsen, A. I. Velter, G. J. MacDonald, et al., “Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators and their preparation and use in the treatment of diseases,” pp. 164, Ortho-Mcneil-Janssen Pharmaceuticals, USA, 2010.
  36. P. Blurton, et al., “Preparation of heteroarylpiperazine derivatives for use in treatment of Alzheimer's disease,” pp.68, Merck & Co., Merck Sharp & Dohme Limited, USA, 2008.
  37. M. A. Findeis, F. Schroeder, T. D. McKee et al., “Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of actaea racemosa,” ACS Chemical Neuroscience, vol. 3, no. 11, pp. 941–951, 2012. View at Publisher · View at Google Scholar
  38. S. J. Haugabook, D. M. Yager, E. A. Eckman, T. E. Golde, S. G. Younkin, and C. B. Eckman, “High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer's amyloid β peptide (Aβ),” Journal of Neuroscience Methods, vol. 108, no. 2, pp. 171–179, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. M. P. Murphy, S. N. Uljon, P. E. Fraser et al., “Presenilin 1 regulates pharmacologically distinct γ-secretase activities: implications for the role of presenilin in γ-secretase cleavage,” Journal of Biological Chemistry, vol. 275, no. 34, pp. 26277–26284, 2000. View at Publisher · View at Google Scholar · View at Scopus
  40. T. A. Lanz, M. J. Karmilowicz, K. M. Wood et al., “Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretase inhibitor, LY-450139,” Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 2, pp. 924–933, 2006. View at Publisher · View at Google Scholar
  41. K. Rogers, et al., “Optimization of a natural product-based class of gamma secretase modulators,” in International Conference on Alzheimer's Disease, Vienna, Austria, 2009.
  42. C. R. Burton, J. E. Meredith, D. M. Barten et al., “The amyloid-β rise and γ-secretase inhibitor potency depend on the level of substrate expression,” Journal of Biological Chemistry, vol. 283, no. 34, pp. 22992–23003, 2008. View at Publisher · View at Google Scholar
  43. J. D. Hughes, J. Blagg, D. A. Price et al., “Physiochemical drug properties associated with in vivo toxicological outcomes,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 17, pp. 4872–4875, 2008. View at Publisher · View at Google Scholar
  44. T. T. Wager, X. Hou, P. R. Verhoest, and A. Villalobos, “Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties,” ACS Chemical Neuroscience, vol. 1, no. 6, pp. 435–449, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. T. T. Wager, R. Y. Chandrasekaran, X. Hou et al., “Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes,” ACS Chemical Neuroscience, vol. 1, no. 6, pp. 420–434, 2010. View at Publisher · View at Google Scholar · View at Scopus
  46. F. Lovering, J. Bikker, and C. Humblet, “Escape from flatland: increasing saturation as an approach to improving clinical success,” Journal of Medicinal Chemistry, vol. 52, no. 21, pp. 6752–6756, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. T. J. Ritchie and S. J. F. Macdonald, “The impact of aromatic ring count on compound developability—are too many aromatic rings a liability in drug design?” Drug Discovery Today, vol. 14, no. 21-22, pp. 1011–1020, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. T. Kimura, K. Kawano, E. Doi, et al., “Preparation of cinnamide, 3-benzylidenepiperidin-2-one, phenylpropynamide compounds as amyloid β production inhibitors,” pp. 679, Eisai, Japan, 2005.
  49. A. Ebke, T. Luebbers, A. Fukumori et al., “Novel γ-secretase enzyme modulators directly target presenilin protein,” Journal of Biological Chemistry, vol. 286, pp. 37181–37186, 2011.
  50. M. S. Wolfe, “gamma-Secretase inhibitors and modulators for Alzheimer's disease,” Journal of Neurochemistry, vol. 120, supplement 1, pp. 89–98, 2012.
  51. Y. Ohki, T. Higo, K. Uemura et al., “Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1,” The EMBO Journal, vol. 30, no. 23, pp. 4815–4824, 2011. View at Publisher · View at Google Scholar
  52. S. Weggen and D. Beher, “Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease,” Alzheimer's Research and Therapy, vol. 4, no. 2, Article ID 9, 2012. View at Publisher · View at Google Scholar
  53. K. Takeo, N. Watanabe, T. Tomita, and T. Iwatsubo, “Contribution of the γ-secretase subunits to the formation of catalytic pore of presenilin 1 protein,” Journal of Biological Chemistry, vol. 287, no. 31, pp. 25834–25843, 2012. View at Publisher · View at Google Scholar