Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease

Journal of Medicinal Chemistry

Volumn 59, Issue 23, 2016, Pages 10435-10450

  Scott, Jack D ^a   Li, Sarah W ^a   Brunskill, Andrew P J ^a   Chen, Xia ^a   Cox, Kathleen ^a   Cumming, Jared N ^a   Forman, Mark ^a   Gilbert, Eric J ^a   Hodgson, Robert A ^a   Hyde, Lynn A ^a   Jiang, Qin ^b   Iserloh, Ulrich ^a   Kazakevich, Irina ^a   Kuvelkar, Reshma ^a   Mei, Hong ^a   Meredith, John ^a   Misiaszek, Jeffrey ^a   Orth, Peter ^a   Rossiter, Lana M ^b   Slater, Meagan ^b   Stone, Julie ^a   Strickland, Corey O ^a   Voigt, Johannes H ^a   Wang, Ganfeng ^a   Wang, Hongwu ^a   Wu, Yusheng ^a   Greenlee, William J ^a   Parker, Eric M ^a   Kennedy, Matthew E ^a   Stamford, Andrew W ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b ALBANY MOLECULAR RESEARCH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 2 (2 FLUORO 5 NITROPHENYL) N METHYLPROPANE 1 SULFONAMIDE; 2 AMINO 2 (3 CHLOROTHIOPHEN 2 YL) N METHYLPROPANE 1 SULFONAMIDE; 4 CHLORO [4 FLUORO 3 (IMINO 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 5 YL)PHENYL]BENZAMIDE; 5 (3 CHLOROTHIOPHEN 2 YL) 3 IMINO 2,5 DIMETHYL 1,2,4 THIADIAZINANE 1,1 DIOXIDE; 5 CHLORO N [4 FLUORO 3 (3 IMINO 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 5 YL)PHENYL]PICOLINAMIDE; 5 [3 CHLORO 5 [5 (PROP 1 YN 1 YL)PYRIDIN 3 YL]THIOPHEN 2 YL] 3 IMINO 2,5 DIMETHYL 1,2,4 THIADIAZINANE 1,1 DIOXIDE; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AMYLOID PRECURSOR PROTEIN; BETA SECRETASE 1; CATHEPSIN D; N (4 METHOXYBENZYL) N METHYLMETHANESULFONAMIDE; N [1 (2 FLUORO 5 NITROPHENYL)ETHYLIDENE] 2 METHYLPROPANE 2 SULNAMIDE; N [1 (3 CHLOROTHIOPHEN 2 YL)ETHYLIDENE] 2 METHYLPROPANE 2 SULFINAMIDE; N [4 FLUORO 3 (IMINO 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 5 YL)PHENYL] 5 METHYLPICOLINAMIDE; N [4 FLUORO 3 (IMINO 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 5 YL)PHENYL]PICOLINAMIDE; TERT BUTYL [5 (2 FLUORO 5 NITROPHENYL) 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 3 YLIDENE]CARBAMATE; TERT BUTYL [5 (3 CHLOROTHIOPHEN 2 YL) 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 3 YLIDENE]CARBAMATE; TERT BUTYL [5 (5 AMINO 2 FLUOROPHENYL) 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 3 YLIDENE]CARBAMATE; TERT BUTYL [5 (5 BROMO 3 CHLOROTHIOPHEN 2 YL) 2,5 DIMETHYL 1,1 DIOXIDO 1,2,4 THIADIAZINAN 3 YLIDENE]CARBAMATE; UNCLASSIFIED DRUG; VERUBECESTAT; SULFOXIDE; THIADIAZINE DERIVATIVE;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ARTICLE; CEREBROSPINAL FLUID; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SYNTHESIS; HEK293 CELL LINE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; IC50; NONHUMAN; PROTEIN EXPRESSION; PROTON NUCLEAR MAGNETIC RESONANCE; RAT; STRUCTURE ACTIVITY RELATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DOG; DOSE RESPONSE; DRUG DEVELOPMENT; MACACA FASCICULARIS; METABOLISM; MOLECULAR MODEL; SPRAGUE DAWLEY RAT; SYNTHESIS;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; CYCLIC S-OXIDES; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; HUMANS; MACACA FASCICULARIS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; THIADIAZINES;

EID: 85003706946     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00307     Document Type: Article

References (66)

1. Wortmann, M. Dementia: a global health priority - highlights from an ADI and World Health Organization report Alzheimer's Res. Ther. 2012, 4, 40-43 10.1186/alzrt143
2. Alzheimer's Disease International. World Alzheimer Report 2015. http://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf.
3. Alzheimer's Association. 2015 Alzheimer's disease facts and figures. Alzheimers Dement. 2015, 332-384.
4. Zemek, F.; Drtinova, L.; Nepovimova, E.; Sepsova, V.; Korabecny, J.; Klimes, J.; Kuca, K. Outcomes of Alzheimer's disease therapy with acetylcholinesterase inhibitors and memantine Expert Opin. Drug Saf. 2014, 13, 759-774 10.1517/14740338.2014.914168
5. Haass, C.; Selkoe, D. J. Soluble protein oligomers in neurodegeneration: Lesson from the Alzheimer's amyloid β-peptide Nat. Rev. Mol. Cell Biol. 2007, 8, 101-112 10.1038/nrm2101
6. Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics Science 2002, 297, 353-356 10.1126/science.1072994
7. Karran, E.; Mercken, M.; De Strooper, B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics Nat. Rev. Drug Discovery 2011, 10, 698-712 10.1038/nrd3505
8. Tanzi, R. E. The genetics of Alzheimer disease Cold Spring Harbor Perspect. Med. 2012, 2, 1-10 10.1101/cshperspect.a006296
9. Citron, M. Alzheimer's disease: strategies for disease modification Nat. Rev. Drug Discovery 2010, 9, 387-398 10.1038/nrd2896
10. Jonsson, T.; Atwal, J. K.; Steinberg, S.; Snaedal, J.; Jonsson, P. V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.; Maloney, J.; Hoyte, K.; Gustafson, A.; Liu, Y.; Lu, Y.; Bhangale, T.; Graham, R. R.; Huttenlocher, J.; Bjornsdottir, G.; Andreassen, O. A.; Jönsson, E. G.; Palotie, A.; Behrens, T. W.; Magnusson, O. T.; Kong, A.; Thorsteinsdottir, U.; Watts, R. J.; Stefansson, K. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline Nature 2012, 488, 96-99 10.1038/nature11283
11. Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen, K. S.; Freedman, S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K. E.; Kawabe, T. T.; Kola, I.; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N. F.; Power, M.; Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G. M.; Shuck, M. E.; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; McConlogue, L. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics Hum. Mol. Genet. 2001, 10, 1317-1324
12. Vassar, R.; Kuhn, P.-H.; Haass, C.; Kennedy, M. E.; Rajendran, L.; Wong, P. C.; Lichtenthaler, S. F. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects J. Neurochem. 2014, 130, 4-28 10.1111/jnc.12715
13. Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J.-C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999, 286, 735-741
14. Sinha, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.; Caccavello, R.; Davis, D.; Doan, M.; Dovey, H. F.; Frigon, N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.; Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, G.; Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S. M.; Wang, S.; Walker, D.; Zhao, J.; McConlogue, L.; John, V. Purification and cloning of amyloid precursor protein β-secretase from human brain Nature 1999, 402, 537-540 10.1038/990114
15. Hussain, I.; Powell, D.; Howlett, D. R.; Tew, D. G.; Meek, T. D.; Chapman, C.; Gloger, I. S.; Murphy, K. E.; Southan, C. D.; Ryan, D. M.; Smith, T. S.; Simmons, D. L.; Walsh, F. S.; Dingwall, C.; Christie, G. Identification of a novel aspartic protease (Asp 2) as β-Secretase Mol. Cell. Neurosci. 1999, 14, 419-427 10.1006/mcne.1999.0811
16. Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.; Tory, M. C.; Pauley, A. M.; Brashler, J. R.; Stratman, N. C.; Mathews, W. R.; Buhl, A. E.; Carter, D. B.; Tomasselli, A. G.; Parodi, L. A.; Heinrikson, R. L.; Gurney, M. E. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity Nature 1999, 402, 533-537 10.1038/990107
17. Lin, X.; Koelsch, G.; Wu, S.; Downs, D.; Dashti, A.; Tang, J. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 1456-1460 10.1073/pnas.97.4.1456
18. Oehlrich, D.; Prokopcova, H.; Gijsen, H. J. M. The evolution of amidine-based brain penetrant BACE1 inhibitors Bioorg. Med. Chem. Lett. 2014, 24, 2033-2045 10.1016/j.bmcl.2014.03.025
19. Yuan, J.; Venkatraman, S.; Zheng, Y.; McKeever, B. M.; Dillard, L. W.; Singh, S. B. Structure-based design of β-site APP cleaving enzyme 1 (BACE) inhibitors for the treatment of Alzheimer's disease. disease J. Med. Chem. 2013, 56, 4156-4180 10.1021/jm301659n
20. Probst, G.; Xu, Y. z. Small-molecule BACE1 inhibitors: a patent literature review (2006-2011) Expert Opin. Ther. Pat. 2012, 22, 511-540 10.1517/13543776.2012.681302
21. Willem, M.; Garratt, A. N.; Novak, B.; Citron, M.; Kaufmann, S.; Rittger, A.; DeStrooper, B.; Saftig, P.; Birchmeier, C.; Haass, C. Control of peripheral nerve myelination by the β-Secretase BACE1 Science 2006, 314, 664-666 10.1126/science.1132341
22. Hu, X.; Hicks, C. W.; He, W.; Wong, P.; Macklin, W. B.; Trapp, B. D.; Yan, R. Bace1 modulates myelination in the central and peripheral nervous system Nat. Neurosci. 2006, 9, 1520-1525 10.1038/nn1797
23. Cheret, C.; Willem, M.; Fricker, F. R.; Wende, H.; Wulf-Goldenberg, A.; Tahirovic, S.; Nave, K.-A.; Saftig, P.; Haass, C.; Garratt, A. N.; Bennett, D. L.; Birchmeier, C. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles EMBO J. 2013, 32, 2015-2028 10.1038/emboj.2013.146
24. McConlogue, L.; Buttini, M.; Anderson, J. P.; Brigham, E. F.; Chen, K. S.; Freedman, S. B.; Games, D.; Johnson-Wood, K.; Lee, M.; Zeller, M.; Liu, W.; Motter, R.; Sinha, S. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice J. Biol. Chem. 2007, 282, 26326-26334 10.1074/jbc.M611687200
25. Wang, Y.-S.; Strickland, C.; Voigt, J. H.; Kennedy, M. E.; Beyer, B. M.; Senior, M. M.; Smith, E. M.; Nechuta, T. L.; Madison, V. S.; Czarniecki, M.; McKittrick, B. A.; Stamford, A. W.; Parker, E. M.; Hunter, J. C.; Greenlee, W. J.; Wyss, D. F. Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel μM leads for the development of nM BACE-1 (β-site APP cleaving enzyme 1) inhibitors J. Med. Chem. 2010, 53, 942-950 10.1021/jm901472u
26. Zhu, Z.; Sun, Z.-Y.; Ye, Y.; Voigt, J.; Strickland, C.; Smith, E. M.; Cumming, J.; Wang, L.; Wong, J.; Wang, Y.-S.; Wyss, D. F.; Chen, X.; Kuvelkar, R.; Kennedy, M. E.; Favreau, L.; Parker, E.; McKittrick, B. A.; Stamford, A.; Czarniecki, M.; Greenlee, W.; Hunter, J. C. Discovery of cyclic acylguanidines as highly potent and selective β-site amyloid cleaving enzyme (BACE) inhibitors: part I-inhibitor design and validation J. Med. Chem. 2010, 53, 951-965 10.1021/jm901408p
27. Stamford, A.; Strickland, C. Inhibitors of BACE for treating Alzheimer's disease: a fragment-based drug discovery story Curr. Opin. Chem. Biol. 2013, 17, 320-328 10.1016/j.cbpa.2013.04.016
28. Cumming, J. N.; Smith, E. M.; Wang, L.; Misiaszek, J.; Durkin, J.; Pan, J.; Iserloh, U.; Wu, Y.; Zhu, Z.; Strickland, C.; Voigt, J.; Chen, X.; Kennedy, M. E.; Kuvelkar, R.; Hyde, L. A.; Cox, K.; Favreau, L.; Czarniecki, M. F.; Greenlee, W. J.; McKittrick, B. A.; Parker, E. M.; Stamford, A. W. Structure based design of iminohydantoin BACE1 inhibitors: identification of an orally available, centrally active BACE1 inhibitor Bioorg. Med. Chem. Lett. 2012, 22, 2444-2449 10.1016/j.bmcl.2012.02.013
29. Stamford, A. W.; Scott, J. D.; Li, S. W.; Babu, S.; Tadesse, D.; Hunter, R.; Wu, Y.; Misiaszek, J.; Cumming, J. N.; Gilbert, E. J.; Huang, C.; McKittrick, B. A.; Hong, L.; Guo, T.; Zhu, Z.; Strickland, C.; Orth, P.; Voigt, J. H.; Kennedy, M. E.; Chen, X.; Kuvelkar, R.; Hodgson, R.; Hyde, L. A.; Cox, K.; Favreau, L.; Parker, E. M.; Greenlee, W. J. Discovery of an orally available, brain penetrant BACE1 inhibitor that affords robust CNS Aβ reduction ACS Med. Chem. Lett. 2012, 3, 897-902 10.1021/ml3001165
30. Mandal, M.; Zhu, Z.; Cumming, J. N.; Liu, X.; Strickland, C.; Mazzola, R. D.; Caldwell, J. P.; Leach, P.; Grzelak, M.; Hyde, L.; Zhang, Q.; Terracina, G.; Zhang, L.; Chen, X.; Kuvelkar, R.; Kennedy, M. E.; Favreau, L.; Cox, K.; Orth, P.; Buevich, A.; Voigt, J.; Wang, H.; Kazakevich, I.; McKittrick, B. A.; Greenlee, W.; Parker, E. M.; Stamford, A. W. Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation J. Med. Chem. 2012, 55, 9331-9345 10.1021/jm301039c
31. Mandal, M.; Wu, Y.; Misiaszek, J.; Li, G.; Buevich, A.; Caldwell, J. P.; Liu, X.; Mazzola, R. D.; Orth, P.; Strickland, C.; Voigt, J.; Wang, H.; Zhu, Z.; Chen, X.; Grzelak, M.; Hyde, L. A.; Kuvelkar, R.; Leach, P. T.; Terracina, G.; Zhang, L.; Zhang, Q.; Michener, M. S.; Smith, B.; Cox, K.; Grotz, D.; Favreau, L.; Mitra, K.; Kazakevich, I.; McKittrick, B. A.; Greenlee, W.; Kennedy, M. E.; Parker, E. M.; Cumming, J. N.; Stamford, A. W. Structure-based design of an iminoheterocyclic β-site amyloid precursor protein cleaving enzyme (BACE) inhibitor that lowers central Aβ in nonhuman primates J. Med. Chem. 2016, 59, 3231-3248 10.1021/acs.jmedchem.5b01995
32. Zhu, Z.; McKittrick, B.; Sun, Z.-Y.; Ye, Y. C.; Voigt, J. H.; Strickland, C.; Smith, E. M.; Stamford, A.; Greenlee, W. J.; Wu, Y.; Iserloh, U.; Mazzola, R.; Caldwell, J.; Cumming, J.; Wang, L.; Guo, T.; Le, T. X. H.; Saionz, K. W.; Babu, S. D.; Hunter, R. C. Preparation of heterocyclic aspartyl protease inhibitors for treating various diseases. WO2005058311A1, 2005.
33. Malamas, M. S.; Erdei, J. J.; Gunawan, I. S.; Zhou, P.; Yan, Y.; Quagliato, D. A. Preparation of amino-5,5-diphenylimidazolone derivatives for inhibition of beta-secretase and treatment of β-amyloid-related diseases. US20050282825A1, 2005.
34. Albert, J. S.; Andisik, D.; Arnold, J.; Brown, D.; Callaghan, O.; Campbell, J.; Carr, R. A. E.; Chessari, G.; Congreve, M. S.; Edwards, P.; Empfield, J. R.; Frederickson, M.; Koether, G. M.; Krumrine, J.; Mauger, R.; Murray, C. W.; Patel, S.; Sylvester, M.; Throner, S. Preparation of substituted 2-aminopyrimidin-4-ones for treating or preventing Aβ-related pathologies. WO2006041404A1, 2006.
35. Ginman, T.; Viklund, J.; Malmström, J.; Blid, J.; Emond, R.; Forsblom, R.; Johansson, A.; Kers, A.; Lake, F.; Sehgelmeble, F.; Sterky, K. J.; Bergh, M.; Lindgren, A.; Johansson, P.; Jeppsson, F.; Fälting, J.; Gravenfors, Y.; Rahm, F. Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity J. Med. Chem. 2013, 56, 4181-4205 10.1021/jm3011349
36. The PSA value was calculated using the method described in Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties J. Med. Chem. 2000, 43, 3714-3717 excluding the contribution from the sulfur atom 10.1021/jm000942e
37. Scott, J. D.; Stamford, A. W.; Gilbert, E. J.; Cumming, J. N.; Iserloh, U.; Misiaszek, J. A.; Li, G. Iminothiadiazine dioxide compounds as BACE inhibitors and their preparation, compositions and use in the treatment of pathologies associated with beta-amyloid protein. WO2011044181A1, 2011.
38. Koike, M.; Nakanishi, H.; Saftig, P.; Ezaki, J.; Isahara, K.; Ohsawa, Y.; Schulz-Schaeffer, W.; Watanabe, T.; Waguri, S.; Kametaka, S.; Shibata, M.; Yamamoto, K.; Kominami, E.; Peters, C.; von Figura, K.; Uchiyama, Y. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons J. Neurosci. 2000, 20, 6898-6906
39. Siintola, E.; Partanen, S.; Strömme, P.; Haapanen, A.; Haltia, M.; Maehlen, J.; Lehesjoki, A.-E.; Tyynelä, J. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis Brain 2006, 129, 1438-1445 10.1093/brain/awl107
40. May, P. C.; Dean, R. A.; Lowe, S. L.; Martenyi, F.; Sheehan, S. M.; Boggs, L. N.; Monk, S. A.; Mathes, B. M.; Mergott, D. J.; Watson, B. M.; Stout, S. L.; Timm, D. E.; LaBell, E. S.; Gonzales, C. R.; Nakano, M.; Jhee, S. S.; Yen, M.; Ereshefsky, L.; Lindstrom, T. D.; Calligaro, D. O.; Cocke, P. J.; Hall, D. G.; Friedrich, S.; Citron, M.; Audia, J. E. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor J. Neurosci. 2011, 31, 16507-16516 10.1523/JNEUROSCI.3647-11.2011
41. Fielden, M. R.; Werner, J.; Jamison, J. A.; Coppi, A.; Hickman, D.; Dunn, R. T., II; Trueblood, E.; Zhou, L.; Afshari, C. A.; Lightfoot-Dunn, R. Retinal toxicity induced by a novel β-secretase inhibitor in the Sprague-Dawley rat Toxicol. Pathol. 2015, 43, 581-592 10.1177/0192623314553804
42. Independent of our work, selectivity of LY2811376 for BACE1 versus CatD was recently reported to be 6-fold. Butler, C. R.; Brodney, M. A.; Beck, E. M.; Barreiro, G.; Nolan, C. E.; Pan, F.; Vajdos, F.; Parris, K.; Varghese, A. H.; Helal, C. J.; Lira, R.; Doran, S. D.; Riddell, D. R.; Buzon, L. M.; Dutra, J. K.; Martinez-Alsina, L. A.; Ogilvie, K.; Murray, J. C.; Young, J. M.; Atchison, K.; Robshaw, A.; Gonzales, C.; Wang, J.; Zhang, Y.; O'Neill, B. T. Discovery of a series of efficient, centrally efficacious BACE1 inhibitors through structure-based drug design J. Med. Chem. 2015, 58, 2678-2702 10.1021/jm501833t
43. Zhu, Z.; McKittrick, B. A.; Sun, Z.-Y.; Ye, Y. C.; Voigt, J. H.; Strickland, C.; Smith, E. M.; Stamford, A.; Greenlee, W. J.; Mazzola, R.; Caldwell, J.; Cumming, J. N.; Wang, L.; Wu, Y.; Iserloh, U.; Guo, T.; Le, T. X. H.; Saionz, K. W.; Babu, S. D.; Hunter, R. C.; Morris, M. L.; Gu, H.; Qian, G.; Tadesse, D. Heterocyclic aspartyl protease inhibitors. US 20060111370, May 25, 2006.
44. Baldwin, E. T.; Bhat, T. N.; Gulnik, S.; Hosur, M. V.; Sowder, R. C., II; Cachau, R. E.; Collins, J.; Silva, A. M.; Erickson, J. W. Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 6796-6800 10.1073/pnas.90.14.6796
45. Rueeger, H.; Lueoend, R.; Rogel, O.; Rondeau, J.-M.; Möbitz, H.; Machauer, R.; Jacobson, L.; Staufenbiel, M.; Desrayaud, S.; Neumann, U. Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid β-peptides J. Med. Chem. 2012, 55, 3364-3386 10.1021/jm300069y
46. Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.; Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein Bioorg. Med. Chem. Lett. 2007, 17, 2697-2702 10.1016/j.bmcl.2007.03.006
47. McDonald, I. M.; Mate, R. A.; Zusi, F. C.; Huang, H.; Post-Munson, D. J.; Ferrante, M. A.; Gallagher, L.; Bertekap, R. L., Jr.; Knox, R. J.; Robertson, B. J.; Harden, D. G.; Morgan, D. G.; Lodge, N. J.; Dworetzky, S. I.; Olson, R. E.; Macor, J. E. Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists Bioorg. Med. Chem. Lett. 2013, 23, 1684-1688 10.1016/j.bmcl.2013.01.070
48. Lerchner, A.; Machauer, R.; Betschart, C.; Veenstra, S.; Rueeger, H.; McCarthy, C.; Tintelnot-Blomley, M.; Jaton, A.-L.; Rabe, S.; Desrayaud, S.; Enz, A.; Staufenbiel, M.; Paganetti, P.; Rondeau, J.-M.; Neumann, U. Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application Bioorg. Med. Chem. Lett. 2010, 20, 603-607 10.1016/j.bmcl.2009.11.092
49. Hyde, L.; Chen, X.; Stahl, L.; Sondey, M.; Scott, J.; Cumming, J.; Stamford, A.; Parker, E.; Kennedy, M. Chronic BACE inhibition dramatically slows the rate of Aβ accumulation and the development of amyloid plaques in young TgCRND8 mice Alzheimer's Dementia 2012, 8, P188 10.1016/j.jalz.2012.05.510
50. Hyde, L.; Cantu, C.; Werner, B.; Chen, X.; Sondey, M.; Chen, M.; Weig, B.; LaShomb, A.; Lu, S.; Hodgson, R.; Scott, J.; Cumming, J.; Stamford, A.; Parker, E.; Kennedy, M. Chronic BACE inhibition halts further age-related increases in brain Aβ and amyloid plaques in aged TgCRND8 mice with established plaques Alzheimer's Dementia 2012, 8, P188 10.1016/j.jalz.2012.05.511
51. Schärfer, C.; Schulz-Gasch, T.; Ehrlich, H.-C.; Guba, W.; Rarey, M.; Stahl, M. Torsion angle preferences in druglike chemical space: a comprehensive guide J. Med. Chem. 2013, 56, 2016-2028 10.1021/jm3016816
52. Kennedy, M. E.; Stamford, A. W.; Chen, X.; Cox, K.; Cumming, J. N.; Dockendorf, M. F.; Egan, M.; Ereshefsky, L.; Hodgson, R. A.; Hyde, L. A.; Jhee, S.; Kleijn, H. J.; Kuvelkar, R.; Li, W.; Mattson, B. A.; Mei, H.; Palcza, J.; Scott, J. D.; Tanen, M.; Troyer, M. D.; Tseng, J. L.; Stone, J. A.; Parker, E. M.; Forman, M. S. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients Sci. Transl. Med. 2016, 8, 363ra150 10.1126/scitranslmed.aad9704
53. Ostermann, N.; Eder, J.; Eidhoff, U.; Zink, F.; Hassiepen, U.; Worpenberg, S.; Maibaum, J.; Simic, O.; Hommel, U.; Gerhartz, B. Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor J. Mol. Biol. 2006, 355, 249-261 10.1016/j.jmb.2005.10.027
54. Kelder, J.; Grootenhuis, P. D. J.; Bayada, D. M.; Delbressine, L. P. C.; Ploemen, J.-P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs Pharm. Res. 1999, 16, 1514-1519 10.1023/A:1015040217741
55. Van de Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J. R.; Raevsky, O. A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors J. Drug Targeting 1998, 6, 151-165 10.3109/10611869808997889
56. Alex, A.; Millan, D. S.; Perez, M.; Wakenhut, F.; Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space MedChemComm 2011, 2, 669-674 10.1039/c1md00093d
57. Tang, H.; Mayersohn, M. A novel model for prediction of human drug clearance by allometric scaling Drug Metab. Dispos. 2005, 33, 1297-1303 For 3, the exponent b was set to 0.75 for all three species used to calculate the projected human dose 10.1124/dmd.105.004143
58. Diller, J. D. In silico hERG modelling: challenges and progress Curr. Comput.-Aided Drug Des. 2009, 5, 106-121 10.2174/157340909788451928
59. Roden, D. M. Drug-induced prolongation of the QT interval N. Engl. J. Med. 2004, 350, 1013-1022 10.1056/NEJMra032426
60. Rochin, L.; Hurbain, I.; Serneels, L.; Fort, C.; Watt, B.; Leblanc, P.; Marks, M. S.; De Strooper, B.; Raposo, G.; van Niel, G. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 10658-10663 10.1073/pnas.1220748110
61. Shimshek, D. R.; Jacobson, L. H.; Kolly, C.; Zamurovic, N.; Balavenkatraman, K. K.; Morawiec, L.; Kreutzer, R.; Schelle, J.; Jucker, M.; Bertschi, B.; Theil, D.; Heier, A.; Bigot, K.; Beltz, K.; Machauer, R.; Brzak, I.; Perrot, L.; Neumann, U. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice Sci. Rep. 2016, 6, 21917 10.1038/srep21917
62. Esterházy, D.; Stützer, I.; Wang, H.; Rechsteiner, M. P.; Beauchamp, J.; Döbeli, H.; Hilpert, H.; Matile, H.; Prummer, M.; Schmidt, A.; Lieske, N.; Boehm, B.; Marselli, L.; Bosco, D.; Kerr-Conte, J.; Aebersold, R.; Spinas, G. A.; Moch, H.; Migliorini, C.; Stoffel, M. BACE2 is a β cell-enriched protease that regulates pancreatic β cell function and mass Cell Metab. 2011, 14, 365-377 10.1016/j.cmet.2011.06.018
63. Velázquez, F.; Arasappan, A.; Chen, K.; Sannigrahi, M.; Venkatraman, S.; McPhail, A. T.; Chan, T.-M.; Shih, N.-Y.; Njoroge, F. G. Stereoselective synthesis of β-substituted β-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines Org. Lett. 2006, 8, 789-792 10.1021/ol053132b
64. Brak, K.; Barrett, K. T.; Ellman, J. A. General one-pot method for the preparation of N-tert-butanesulfinylamine diastereomer mixtures as standards for stereoselectivity determinations J. Org. Chem. 2009, 74, 3606-3608 10.1021/jo900353p
65. Huang, B.-S.; Chello, P. L.; Yip, L.; Parham, J. C. Synthesis and properties of the sulfonyl analogues of 4(5)-aminoimidazole-5(4)-carboxamide, 4(5)-(formylamino)imidazole-5(4)-carboxamide, guanine, and xanthine J. Med. Chem. 1980, 23, 575-577 10.1021/jm00179a021
66. A manufacturing route to verubecestat is described in Thaisrivongs, D. A.; Miller, S. P.; Molinaro, C.; Chen, Q.; Song, Z. J.; Tan, L.; Chen, L.; Wenyong Chen, W.; Lekhal, A.; Pulicare, S. K.; Xu, Y. Synthesis of verubecestat (MK-8931), a BACE1 inhibitor for the treatment of Alzheimer's disease Org. Lett. 2016, 10.1021/acs.orglett.6b01793