The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aβ42. Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aβ42 and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity. 1. Introduction Gamma-secretase (γ-secretase) is required for the production of amyloid beta peptides (Aβ) and decreasing Aβ production as a disease modifying approach for the treatment of Alzheimer’s disease (AD) has received intense interest. The initial focus was on the discovery of compounds that would decrease γ-secretase activity. γ-Secretase cleaves the membrane bound C-terminal domain (C99) of APP at the site to produce the intracellular domain, AICD. The enzyme then makes sequential cuts of the remaining intramembrane APP fragment at each turn of the alpha helix (every 3-4 amino acids) until Aβ peptides are formed and released into the extracellular space [1–3]. This protein processivity produces Aβ peptides that vary in size, from 43–34 amino acids in length [4, 5]. In Alzheimer’s disease, a greater number of the longer forms of Aβ, including Aβ42 and Aβ43, or a high ratio of the long peptides to the shorter forms, appear to occur [6]. These longer Aβ peptides readily oligomerize, forming toxic species, as well as becoming the seeds for amyloid plaques [7, 8]. The full inhibition of γ-secretase appeared to
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
