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The Design, Development, and Evaluation of BACE1 Inhibitors for the Treatment of Alzheimer’s Disease

  • Arun K. GhoshEmail author
  • Emilio L. Cárdenas
  • Heather L. Osswald
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 24)

Abstract

Alzheimer’s disease (AD) is a very serious public health problem. Currently, there is no effective treatment for AD. Among the many biochemical targets for AD drug development, β-secretase (BACE1, memapsin 2) continues to be a promising drug discovery target for AD therapy. This proteolytic enzyme is a membrane-anchored aspartic acid protease that is responsible for the initial step of amyloid precursor protein (APP) cleavage, leading to the production of neurotoxic amyloid-β (Aβ) peptides in the brain. Since its identification and structural elucidation in 1999, extensive research efforts have led to the development of many promising classes of inhibitors against this protease. Structure-based design strategies led to the evolution of many small-molecule, peptidomimetic, and nonpeptide BACE1 inhibitors that have now overcome the key development challenges including selectivity and brain penetration. To date, 13 BACE1 drug candidates have been brought to clinical trials, and a number of them have advanced to phase II/III human trials. This chapter illustrates structure-based evolution of various classes of BACE inhibitors. Also, it provides a perspective on BACE1 inhibitor drugs for the treatment of AD patients.

Keywords

β-Secretase Alzheimer’s disease BACE1 BACE1 inhibitor Drug design Enzyme inhibitors Memapsin 2 Nonpeptide inhibitor Peptidomimetic inhibitor Structure-activity relationship 

Abbreviations

Amyloid-β protein

AD

Alzheimer’s Disease

ADAS

Alzheimer’s Disease Assessment Scale

ADAS-Cog

Alzheimer’s Disease Assessment Scale-Cognitive Subscale

ADCS

Alzheimer’s Disease Cooperative Study

ADCS-ADL

Alzheimer’s Disease Cooperative Study-Activities of Daily Living

ADCS-PACC

Alzheimer’s Disease Cooperative Study-Preclinical Alzheimer’s Cognitive Composite

ADME

Absorption distribution, metabolism, and excretion

APP

Amyloid precursor protein

BACE1

β-Site amyloid precursor protein-cleaving enzyme 1

BACE2

β-Site amyloid precursor protein-cleaving enzyme 2

BBB

Blood–brain barrier

CatD

Cathepsin D

CCS-3D

3-Domain Composite Cognition Score

CDR

Clinical Dementia Rating Scale

CDR-SB

Clinical Dementia Rating Sum of Boxes

CFI

Cognitive Function Instrument

CNS

Central nervous system

CSF

Cerebrospinal fluid

C-SSRS

Columbia-Suicide Severity Rating Scale

ECG

Electrocardiogram

FDA

Food and Drug Administration

HIV

Human immunodeficiency virus

HTS

High-throughput screening

IC50

50% inhibitory concentration

Ki

Inhibitory constant

MMSE

Mini Mental State Examination

MRI

Magnetic resonance imaging

MWM

Morris water maze

NMDA

N-Methyl d-aspartate

NPI

Neuropsychiatric Inventory

NTB

Neuropsychological Test Battery

PET

Positron emission tomography

Pgp

P-glycoprotein

QT

Q-wave to T-wave interval

sAPPα

Soluble amyloid precursor protein α-fragment

sAPPβ

Soluble amyloid precursor protein β-fragment

SAR

Structure-activity relationship

Notes

Acknowledgment

The authors’ work in the article was supported by the National Institutes of Health. We would also like to thank Ms. Anne Veitschegger and Mr. Luke Kassekert (both Purdue University) for their helpful discussions.

References

  1. 1.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766Google Scholar
  2. 2.
    Alzheimer’s Association (2012) Alzheimer’s disease facts and figures. Alzheimers Dement 8(2):131–168. doi: 10.1016/j.jalz.2012.02.001
  3. 3.
    Alzheimer’s Association (2013) Alzheimer’s disease facts and figures. Alzheimers Dement 9(2):208–245. doi: 10.1016/j.jalz.2013.02.003
  4. 4.
    Alzheimers.net (2016) 2016 Alzheimer’s statistics. http://www.alzheimers.net/resources/alzheimers-statistics/. Accessed 20 May 2016
  5. 5.
    Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. AlzheAlzheimers Res Ther 6(4):37. doi: 10.1186/alzrt269 CrossRefGoogle Scholar
  6. 6.
    Anand P, Singh B (2013) A review on cholinesterase inhibitors for Alzheimer’s disease. Arch Pharm Res 36(4):375–399. doi: 10.1007/s12272-013-0036-3 CrossRefGoogle Scholar
  7. 7.
    Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE (2008) Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin Interv Aging 3(2):211–225Google Scholar
  8. 8.
    Olivares D, Deshpande VK, Shi Y, Lahiri DK, Greig NH, Rogers JT, Huang X (2012) N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer’s disease, vascular dementia and Parkinson’s disease. Curr Alzheimer Res 9(6):746–758. doi: 10.2174/156720512801322564 CrossRefGoogle Scholar
  9. 9.
    Hyde C, Peters J, Bond M, Rogers G, Hoyle M, Anderson R, Jeffreys M, Davis S, Thokala P, Moxham T (2013) Evolution of the evidence on the effectiveness and cost-effectiveness of acetylcholinesterase inhibitors and memantine for Alzheimer’s disease: systematic review and economic model. Age Ageing 42(1):14–20. doi: 10.1093/ageing/afs165 CrossRefGoogle Scholar
  10. 10.
    Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399(6738):A23–A31. doi: 10.1038/399a023 CrossRefGoogle Scholar
  11. 11.
    Ghosh AK, Osswald HL (2014) BACE1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease. Chem Soc Rev 43(19):6765–6813. doi: 10.1039/c3cs60460h CrossRefGoogle Scholar
  12. 12.
    Butini S, Brogi S, Novellino E, Campiani G, Ghosh AK, Brindisi M, Gemma S (2013) The structural evolution of β-secretase inhibitors: a focus on the development of small-molecule inhibitors. Curr Top Med Chem 13(15):1787–1807. doi: 10.2174/15680266113139990137 CrossRefGoogle Scholar
  13. 13.
    Citron M (2010) Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 9(5):387–398. doi: 10.1038/nrd2896 CrossRefGoogle Scholar
  14. 14.
    Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Aβ causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45(5):675–688. doi: 10.1016/j.neuron.2005.01.040 CrossRefGoogle Scholar
  15. 15.
    Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD (2000) Correlation between elevated levels of amyloid-β peptide in the brain and cognitive decline. J Am Med Assoc 283(12):1571–1577. doi: 10.1001/jama.283.12.1571 CrossRefGoogle Scholar
  16. 16.
    Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, Vassar R (2007) BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26(1):134–145. doi: 10.1016/j.nbd.2006.12.008 CrossRefGoogle Scholar
  17. 17.
    Wolfe MS (2008) Inhibition and modulation of γ-secretase for Alzheimer’s disease. Neurotherapeutics 5(3):391–398. doi: 10.1016/j.nurt.2008.05.010 CrossRefGoogle Scholar
  18. 18.
    Sinha S (2010) BACE: a (almost) perfect target for staving off Alzheimer’s disease. In: Ghosh AK (ed) Aspartic acid proteases as therapeutic targets, vol 45, Methods and principles in medicinal chemistry. Wiley-VCH, Weinheim, pp 393–412Google Scholar
  19. 19.
    Tang J, Hong L, Ghosh AK (2010) The discovery of β-secretase and development toward a clinical inhibitor for AD: an exciting academic collaboration. In: Ghosh AK (ed) Aspartic acid proteases as therapeutic targets, vol 45, Methods and principles in medicinal chemistry. Wiley-VCH, Weinheim, pp 413–440Google Scholar
  20. 20.
    Selkoe DJ (1994) Cell biology of the amyloid β-protein precursor and the mechanism of Alzheimer’s disease. Annu Rev Cell Biol 10:373–403. doi: 10.1146/annurev.cb.10.110194.002105 CrossRefGoogle Scholar
  21. 21.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356. doi: 10.1126/science.1072994 CrossRefGoogle Scholar
  22. 22.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791. doi: 10.1126/science.1074069 CrossRefGoogle Scholar
  23. 23.
    Selkoe DJ (2000) The origins of Alzheimer’s disease: a is for amyloid. J Am Med Assoc 283(12):1615–1617. doi: 10.1001/jama.283.12.1615 CrossRefGoogle Scholar
  24. 24.
    Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G (1999) Identification of a novel aspartic protease (Asp2) as β-secretase. Mol Cell Neurosci 14(6):419–427. doi: 10.1006/mcne.1999.0811 CrossRefGoogle Scholar
  25. 25.
    Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, 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 SM, Wang S, Walker D, Zhao J, McConlogue L, John V (1999) Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402(6761):537–540. doi: 10.1038/990114 CrossRefGoogle Scholar
  26. 26.
    Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (2000) Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc Natl Acad Sci U S A 97(4):1456–1460. doi: 10.1073/pnas.97.4.1456 CrossRefGoogle Scholar
  27. 27.
    Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) β-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741. doi: 10.1126/science.286.5440.735 CrossRefGoogle Scholar
  28. 28.
    Sinha S, Lieberburg I (1999) Cellular mechanisms of β-amyloid production and secretion. Proc Natl Acad Sci U S A 96(20):11049–11053. doi: 10.1073/pnas.96.20.11049 CrossRefGoogle Scholar
  29. 29.
    Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci 4(3):233–234. doi: 10.1038/85064 CrossRefGoogle Scholar
  30. 30.
    Roberds SL, Anderson JP, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Keappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L (2001) BACE Knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 10(12):1317–1324. doi: 10.1093/hmg/10.12.1317 CrossRefGoogle Scholar
  31. 31.
    Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat Neurosci 4(3):231–232. doi: 10.1038/85059 CrossRefGoogle Scholar
  32. 32.
    Iserloh U, Cumming JN (2010) Peptidomimetic BACE1 inhibitors for treatment of Alzheimer’s disease: design and evolution. In: Ghosh AK (ed) Aspartic acid proteases as therapeutic targets, vol 45, Methods and principles in medicinal chemistry. Wiley-VCH, Weinheim, pp 441–479Google Scholar
  33. 33.
    Nishitomi K, Sakaguchi G, Horikoshi Y, Gray AJ, Maeda M, Hirata-Fukae C, Becker AG, Hosono M, Sakaguchi I, Minami SS, Nakajima Y, Li HF, Takeyama C, Kihara T, Ota A, Wong PC, Aisen PS, Kato A, Kinoshita N, Matsuoka Y (2006) BACE1 inhibition reduces endogenous Aβ and alters APP processing in wild-type mice. J Neurochem 99(6):1555–1563. doi: 10.1111/j.1471-4159.2006.04178.x CrossRefGoogle Scholar
  34. 34.
    Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 9(12):1520–1525. doi: 10.1038/nn1797 CrossRefGoogle Scholar
  35. 35.
    Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, Wilson CG, Yan R (2010) BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 30(26):8819–8829. doi: 10.1523/JNEUROSCI.1334-10.2010 CrossRefGoogle Scholar
  36. 36.
    Kobayashi D, Zeller M, Cole T, Buttini M, McConlogue L, Sinha S, Freedman S, Morris RG, Chen KS (2008) BACE1 gene deletion: impact on behavioral function in a model of Alzheimer’s disease. Neurobiol Aging 29(6):861–873. doi: 10.1016/j.neurobiolaging.2007.01.002 CrossRefGoogle Scholar
  37. 37.
    Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R (2012) beta-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem 287(46):38408–38425. doi: 10.1074/jbc.M112.415505 CrossRefGoogle Scholar
  38. 38.
    Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25(50):11693–11709CrossRefGoogle Scholar
  39. 39.
    Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci U S A 105(14):5585–5590. doi: 10.1073/pnas.0710373105 CrossRefGoogle Scholar
  40. 40.
    LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci 8(7):499–509CrossRefGoogle Scholar
  41. 41.
    Chang WP, Koelsch G, Wong S, Downs D, Da H, Weerasena V, Gordon B, Devasamudram T, Bilcer G, Ghosh AK, Tang J (2004) In vivo inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors. J Neurochem 89(6):1409–1416. doi: 10.1111/j.1471-4159.2004.02452.x CrossRefGoogle Scholar
  42. 42.
    Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T, Schwille P, Schulz JB, Schroeder C, Simons M, Jennings G, Knolker HJ, Simons K (2008) Efficient inhibition of the Alzheimer’s disease β-secretase by membrane targeting. Science 320(5875):520–523. doi: 10.1126/science.1156609 CrossRefGoogle Scholar
  43. 43.
    Meredith JE Jr, Thompson LA, Toyn JH, Marcin L, Barten DM, Marcinkeviciene J, Kopcho L, Kim Y, Lin A, Guss V, Burton C, Iben L, Polson C, Cantone J, Ford M, Drexler D, Fiedler T, Lentz KA, Grace JE Jr, Kolb J, Corsa J, Pierdomenico M, Jones K, Olson RE, Macor JE, Albright CF (2008) P-glycoprotein efflux and other factors limit brain amyloid-β reduction by β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice. J Pharmacol Exp Ther 326(2):502–513. doi: 10.1124/jpet.108.138974 CrossRefGoogle Scholar
  44. 44.
    Hong L, Tang J (2004) Flap position of free memapsin 2 (β-secretase), a model for flap opening in aspartic protease catalysis. Biochemistry 43(16):4689–4695. doi: 10.1021/bi0498252 CrossRefGoogle Scholar
  45. 45.
    Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J (2000) Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science 290(5489):150–153. doi: 10.1126/science.290.5489.150 CrossRefGoogle Scholar
  46. 46.
    Hong L, Turner RT 3rd, Koelsch G, Shin D, Ghosh AK, Tang J (2002) Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3. Biochemistry 41(36):10963–10967. doi: 10.1021/bi026232n CrossRefGoogle Scholar
  47. 47.
    Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R (2000) Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem 275(27):20647–20651. doi: 10.1074/jbc.M002688200 CrossRefGoogle Scholar
  48. 48.
    Ghosh AK, Brindisi M, Tang J (2012) Developing β-secretase inhibitors for treatment of Alzheimer’s disease. J Neurochem 120(Suppl 1):71–83. doi: 10.1111/j.1471-4159.2011.07476.x CrossRefGoogle Scholar
  49. 49.
    Turner RT 3rd, Koelsch G, Hong L, Castanheira P, Ermolieff J, Ghosh AK, Tang J (2001) Subsite specificity of memapsin 2 (β-secretase): implications for inhibitor design. Biochemistry 40(34):10001–10006. doi: 10.1021/bi015546s CrossRefGoogle Scholar
  50. 50.
    Ghosh AK, Shin DW, Downs D, Koelsch G, Lin XL, Ermolieff J, Tang J (2000) Design of potent inhibitors for human brain memapsin 2 (β-secretase). J Am Chem Soc 122(14):3522–3523. doi: 10.1021/Ja000300g CrossRefGoogle Scholar
  51. 51.
    Ghosh AK, Bilcer G, Harwood C, Kawahama R, Shin D, Hussain KA, Hong L, Loy JA, Nguyen C, Koelsch G, Ermolieff J, Tang J (2001) Structure-based design: potent inhibitors of human brain memapsin 2 (β-secretase). J Med Chem 44(18):2865–2868. doi: 10.1021/jm0101803 CrossRefGoogle Scholar
  52. 52.
    Ghosh AK, Kumaragurubaran N, Hong L, Lei H, Hussain KA, Liu CF, Devasamudram T, Weerasena V, Turner R, Koelsch G, Bilcer G, Tang J (2006) Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (β-secretase) inhibitors. J Am Chem Soc 128(16):5310–5311. doi: 10.1021/ja058636j CrossRefGoogle Scholar
  53. 53.
    Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni SS, Xu XM, Chang WP, Weerasena V, Turner R, Koelsch G, Bilcer G, Tang J (2007) Design, synthesis, and X-ray structure of potent memapsin 2 (β-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem 50(10):2399–2407. doi: 10.1021/Jm061338s CrossRefGoogle Scholar
  54. 54.
    Bjorklund C, Oscarson S, Benkestock K, Borkakoti N, Jansson K, Lindberg J, Vrang L, Hallberg A, Rosenquist A, Samuelsson B (2010) Design and synthesis of potent and selective BACE-1 inhibitors. J Med Chem 53(4):1458–1464. doi: 10.1021/jm901168f CrossRefGoogle Scholar
  55. 55.
    Ghosh AK, Chapsal BD, Mitsuya H (2010) Darunavir, a new PI with dual mechanism: from a novel drug design concept to new hope against drug-resistant HIV. In: Ghosh AK (ed) Aspartic acid proteases as therapeutic targets, vol 45, Methods and principles in medicinal chemistry. Wiley-VCH, Weinheim, pp 204–243. doi: 10.1002/9783527630943.ch8 CrossRefGoogle Scholar
  56. 56.
    Ghosh AK, Anderson DD, Mitsuya H (2010) The FDA approved HIV-1 protease inhibitors for treatment of HIV/AIDS. In: Burger’s medicinal chemistry and drug discovery. John Wiley & Sons, Inc., pp 1–74. doi: 10.1002/0471266949.bmc224
  57. 57.
    Tamamura H, Kato T, Otaka A, Fujii N (2003) Synthesis of potent β-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure-activity relationship studies. Org Biomol Chem 1(14):2468–2473. doi: 10.1039/b304842j CrossRefGoogle Scholar
  58. 58.
    Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi S, Simon AJ, Kuo L, Vacca JP (2004) Structure-based design of potent and selective cell-permeable inhibitors of human β-secretase (BACE-1). J Med Chem 47(26):6447–6450. doi: 10.1021/jm049379g CrossRefGoogle Scholar
  59. 59.
    Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, Ghosh AK, Tang J (2011) β-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J 25(2):775–784. doi: 10.1096/fj.10-167213 CrossRefGoogle Scholar
  60. 60.
    Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni S, Xu X, Miller HB, Reddy DS, Weerasena V, Turner R, Chang W, Koelsch G, Tang J (2008) Potent memapsin 2 (β-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorg Med Chem Lett 18(3):1031–1036. doi: 10.1016/j.bmcl.2007.12.028 CrossRefGoogle Scholar
  61. 61.
    Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G (2008) BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg Med Chem Lett 18(3):1022–1026. doi: 10.1016/j.bmcl.2007.12.020 CrossRefGoogle Scholar
  62. 62.
    Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, Hawkins J, Howes C, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G (2009) Second generation of BACE-1 inhibitors part 3: towards non hydroxyethylamine transition state mimetics. Bioorg Med Chem Lett 19(13):3674–3678. doi: 10.1016/j.bmcl.2009.03.149 CrossRefGoogle Scholar
  63. 63.
    Rajapakse HA, Nantermet PG, Selnick HG, Munshi S, McGaughey GB, Lindsley SR, Young MB, Lai MT, Espeseth AS, Shi XP, Colussi D, Pietrak B, Crouthamel MC, Tugusheva K, Huang Q, Xu M, Simon AJ, Kuo L, Hazuda DJ, Graham S, Vacca JP (2006) Discovery of oxadiazoyl tertiary carbinamine inhibitors of β-secretase (BACE-1). J Med Chem 49(25):7270–7273. doi: 10.1021/jm061046r CrossRefGoogle Scholar
  64. 64.
    Sankaranarayanan S, Holahan MA, Colussi D, Crouthamel MC, Devanarayan V, Ellis J, Espeseth A, Gates AT, Graham SL, Gregro AR, Hazuda D, Hochman JH, Holloway K, Jin L, Kahana J, Lai MT, Lineberger J, McGaughey G, Moore KP, Nantermet P, Pietrak B, Price EA, Rajapakse H, Stauffer S, Steinbeiser MA, Seabrook G, Selnick HG, Shi XP, Stanton MG, Swestock J, Tugusheva K, Tyler KX, Vacca JP, Wong J, Wu G, Xu M, Cook JJ, Simon AJ (2009) First demonstration of cerebrospinal fluid and plasma Aβ lowering with oral administration of a β-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates. J Pharmacol Exp Ther 328(1):131–140. doi: 10.1124/jpet.108.143628 CrossRefGoogle Scholar
  65. 65.
    Nantermet PG, Rajapakse HA, Stanton MG, Stauffer SR, Barrow JC, Gregro AR, Moore KP, Steinbeiser MA, Swestock J, Selnick HG, Graham SL, McGaughey GB, Colussi D, Lai MT, Sankaranarayanan S, Simon AJ, Munshi S, Cook JJ, Holahan MA, Michener MS, Vacca JP (2009) Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing. ChemMedChem 4(1):37–40. doi: 10.1002/cmdc.200800308 CrossRefGoogle Scholar
  66. 66.
    Stanton MG, Stauffer SR, Gregro AR, Steinbeiser M, Nantermet P, Sankaranarayanan S, Price EA, Wu G, Crouthamel MC, Ellis J, Lai MT, Espeseth AS, Shi XP, Jin L, Colussi D, Pietrak B, Huang Q, Xu M, Simon AJ, Graham SL, Vacca JP, Selnick H (2007) Discovery of isonicotinamide derived β-secretase inhibitors: in vivo reduction of β-amyloid. J Med Chem 50(15):3431–3433. doi: 10.1021/jm070272d CrossRefGoogle Scholar
  67. 67.
    Coburn CA, Stachel SJ, Jones KG, Steele TG, Rush DM, DiMuzio J, Pietrak BL, Lai MT, Huang Q, Lineberger J, Jin L, Munshi S, Katharine Holloway M, Espeseth A, Simon A, Hazuda D, Graham SL, Vacca JP (2006) BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres. Bioorg Med Chem Lett 16(14):3635–3638. doi: 10.1016/j.bmcl.2006.04.076 CrossRefGoogle Scholar
  68. 68.
    Ghosh AK, Venkateswara Rao K, Yadav ND, Anderson DD, Gavande N, Huang X, Terzyan S, Tang J (2012) Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure. J Med Chem 55(21):9195–9207. doi: 10.1021/jm3008823 CrossRefGoogle Scholar
  69. 69.
    Ghosh AK, Devasamudram T, Hong L, DeZutter C, Xu X, Weerasena V, Koelsch G, Bilcer G, Tang J (2005) Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase). Bioorg Med Chem Lett 15(1):15–20. doi: 10.1016/j.bmcl.2004.10.084 CrossRefGoogle Scholar
  70. 70.
    Machauer R, Laumen K, Veenstra S, Rondeau JM, Tintelnot-Blomley M, Betschart C, Jaton AL, Desrayaud S, Staufenbiel M, Rabe S, Paganetti P, Neumann U (2009) Macrocyclic peptidomimetic β-secretase (BACE-1) inhibitors with activity in vivo. Bioorg Med Chem Lett 19(5):1366–1370. doi: 10.1016/j.bmcl.2009.01.055 CrossRefGoogle Scholar
  71. 71.
    Stachel SJ, Coburn CA, Sankaranarayanan S, Price EA, Wu G, Crouthamel M, Pietrak BL, Huang Q, Lineberger J, Espeseth AS, Jin L, Ellis J, Holloway MK, Munshi S, Allison T, Hazuda D, Simon AJ, Graham SL, Vacca JP (2006) Macrocyclic inhibitors of β-secretase: functional activity in an animal model. J Med Chem 49(21):6147–6150. doi: 10.1021/jm060884i CrossRefGoogle Scholar
  72. 72.
    Cole DC, Bursavich MG (2010) Nonpeptide BACE1 inhibitors: design and synthesis. In: Ghosh AK (ed) Aspartic acid proteases as therapeutic targets, vol 45, Methods and principles in medicinal chemistry. Wiley-VCH, Weinheim, pp 481–509Google Scholar
  73. 73.
    Cole DC, Manas ES, Stock JR, Condon JS, Jennings LD, Aulabaugh A, Chopra R, Cowling R, Ellingboe JW, Fan KY, Harrison BL, Hu Y, Jacobsen S, Jin G, Lin L, Lovering FE, Malamas MS, Stahl ML, Strand J, Sukhdeo MN, Svenson K, Turner MJ, Wagner E, Wu J, Zhou P, Bard J (2006) Acylguanidines as small-molecule β-secretase inhibitors. J Med Chem 49(21):6158–6161. doi: 10.1021/jm0607451 CrossRefGoogle Scholar
  74. 74.
    Gerritz SW, Zhai W, Shi S, Zhu S, Toyn JH, Meredith JE Jr, Iben LG, Burton CR, Albright CF, Good AC, Tebben AJ, Muckelbauer JK, Camac DM, Metzler W, Cook LS, Padmanabha R, Lentz KA, Sofia MJ, Poss MA, Macor JE, Thompson LA 3rd (2012) Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis. J Med Chem 55(21):9208–9223. doi: 10.1021/jm300931y CrossRefGoogle Scholar
  75. 75.
    Thomas AA, Hunt KW, Volgraf M, Watts RJ, Liu X, Vigers G, Smith D, Sammond D, Tang TP, Rhodes SP, Metcalf AT, Brown KD, Otten JN, Burkard M, Cox AA, Do MKG, Dutcher D, Rana S, DeLisle RK, Regal K, Wright AD, Groneberg R, Scearce-Levie K, Siu M, Purkey HE, Lyssikatos JP, Gunawardana IW (2014) Discovery of 7-tetrahydropyran-2-yl chromans: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system. J Med Chem 57(3):878–902. doi: 10.1021/jm401635n CrossRefGoogle Scholar
  76. 76.
    Congreve M, Aharony D, Albert J, Callaghan O, Campbell J, Carr RA, Chessari G, Cowan S, Edwards PD, Frederickson M, McMenamin R, Murray CW, Patel S, Wallis N (2007) Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of β-secretase. J Med Chem 50(6):1124–1132. doi: 10.1021/jm061197u CrossRefGoogle Scholar
  77. 77.
    Malamas MS, Barnes K, Hui Y, Johnson M, Lovering F, Condon J, Fobare W, Solvibile W, Turner J, Hu Y, Manas ES, Fan K, Olland A, Chopra R, Bard J, Pangalos MN, Reinhart P, Robichaud AJ (2010) Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors. Bioorg Med Chem Lett 20(7):2068–2073. doi: 10.1016/j.bmcl.2010.02.075 CrossRefGoogle Scholar
  78. 78.
    Hills ID, Holloway MK, de Leon P, Nomland A, Zhu H, Rajapakse H, Allison TJ, Munshi SK, Colussi D, Pietrak BL, Toolan D, Haugabook SJ, Graham SL, Stachel SJ (2009) A conformational constraint improves a β-secretase inhibitor but for an unexpected reason. Bioorg Med Chem Lett 19(17):4993–4995. doi: 10.1016/j.bmcl.2009.07.071 CrossRefGoogle Scholar
  79. 79.
    Malamas MS, Erdei J, Gunawan I, Barnes K, Johnson M, Hui Y, Turner J, Hu Y, Wagner E, Fan K, Olland A, Bard J, Robichaud AJ (2009) Aminoimidazoles as potent and selective human β-secretase (BACE1) inhibitors. J Med Chem 52(20):6314–6323. doi: 10.1021/jm9006752 CrossRefGoogle Scholar
  80. 80.
    Swahn BM, Holenz J, Kihlstrom J, Kolmodin K, Lindstrom J, Plobeck N, Rotticci D, Sehgelmeble F, Sundstrom M, Berg S, Falting J, Georgievska B, Gustavsson S, Neelissen J, Ek M, Olsson LL, Berg S (2012) Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy. Bioorg Med Chem Lett 22(5):1854–1859. doi: 10.1016/j.bmcl.2012.01.079 CrossRefGoogle Scholar
  81. 81.
    Malamas MS, Erdei J, Gunawan I, Turner J, Hu Y, Wagner E, Fan K, Chopra R, Olland A, Bard J, Jacobsen S, Magolda RL, Pangalos M, Robichaud AJ (2010) Design and synthesis of 5,5′-disubstituted aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors. J Med Chem 53(3):1146–1158. doi: 10.1021/jm901414e CrossRefGoogle Scholar
  82. 82.
    Caldwell JP, Mazzola RD, Durkin J, Chen J, Chen X, Favreau L, Kennedy M, Kuvelkar R, Lee J, McHugh N, McKittrick B, Orth P, Stamford A, Strickland C, Voigt J, Wang L, Zhang L, Zhang Q, Zhu Z (2014) Discovery of potent iminoheterocycle BACE1 inhibitors. Bioorg Med Chem Lett 24(23):5455–5459. doi: 10.1016/j.bmcl.2014.10.006 CrossRefGoogle Scholar
  83. 83.
    Egbertson M, McGaughey GB, Pitzenberger SM, Stauffer SR, Coburn CA, Stachel SJ, Yang W, Barrow JC, Neilson LA, McWherter M, Perlow D, Fahr B, Munshi S, Allison TJ, Holloway K, Selnick HG, Yang Z, Swestock J, Simon AJ, Sankaranarayanan S, Colussi D, Tugusheva K, Lai M-T, Pietrak B, Haugabook S, Jin L, Chen IW, Holahan M, Stranieri-Michener M, Cook JJ, Vacca J, Graham SL (2015) Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency. Bioorg Med Chem Lett 25(21):4812–4819. doi: 10.1016/j.bmcl.2015.06.082 CrossRefGoogle Scholar
  84. 84.
    Woltering TJ, Wostl W, Hilpert H, Rogers-Evans M, Pinard E, Mayweg A, Gobel M, Banner DW, Benz J, Travagli M, Pollastrini M, Marconi G, Gabellieri E, Guba W, Mauser H, Andreini M, Jacobsen H, Power E, Narquizian R (2013) BACE1 inhibitors: a head group scan on a series of amides. Bioorg Med Chem Lett 23(14):4239–4243. doi: 10.1016/j.bmcl.2013.05.003 CrossRefGoogle Scholar
  85. 85.
    Hilpert H, Guba W, Woltering TJ, Wostl W, Pinard E, Mauser H, Mayweg AV, Rogers-Evans M, Humm R, Krummenacher D, Muser T, Schnider C, Jacobsen H, Ozmen L, Bergadano A, Banner DW, Hochstrasser R, Kuglstatter A, David-Pierson P, Fischer H, Polara A, Narquizian R (2013) β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer’s disease. J Med Chem 56(10):3980–3995. doi: 10.1021/jm400225m CrossRefGoogle Scholar
  86. 86.
    Epstein O, Bryan MC, Cheng AC, Derakhchan K, Dineen TA, Hickman D, Hua Z, Human JB, Kreiman C, Marx IE, Weiss MM, Wahl RC, Wen PH, Whittington DA, Wood S, Zheng XM, Fremeau RT, White RD, Patel VF (2014) Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors. J Med Chem 57(23):9796–9810. doi: 10.1021/jm501266w CrossRefGoogle Scholar
  87. 87.
    Cheng Y, Brown J, Judd TC, Lopez P, Qian W, Powers TS, Chen JJ, Bartberger MD, Chen K, Dunn RT, Epstein O, Fremeau RT, Harried S, Hickman D, Hitchcock SA, Luo Y, Minatti AE, Patel VF, Vargas HM, Wahl RC, Weiss MM, Wen PH, White RD, Whittington DA, Zheng XM, Wood S (2015) An orally available BACE1 inhibitor that affords robust CNS Aβ reduction without cardiovascular liabilities. ACS Med Chem Lett 6(2):210–215. doi: 10.1021/ml500458t CrossRefGoogle Scholar
  88. 88.
    Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, Reynolds CH, Tounge BA, Luo C, Scott MK, Huang Y, Braeken M, Pieters SM, Berthelot DJ, Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J, Alexander RS, Brenneman DE, Reitz AB (2007) 2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): use of structure based design to convert a micromolar hit into a nanomolar lead. J Med Chem 50(18):4261–4264. doi: 10.1021/jm0705408 CrossRefGoogle Scholar
  89. 89.
    Ghosh AK, Pandey S, Gangarajula S, Kulkarni S, Xu X, Rao KV, Huang X, Tang J (2012) Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors. Bioorg Med Chem Lett 22(17):5460–5465. doi: 10.1016/j.bmcl.2012.07.043 CrossRefGoogle Scholar
  90. 90.
    Cheng Y, Judd TC, Bartberger MD, Brown J, Chen K, Fremeau RT Jr, Hickman D, Hitchcock SA, Jordan B, Li V, Lopez P, Louie SW, Luo Y, Michelsen K, Nixey T, Powers TS, Rattan C, Sickmier EA, St Jean DJ Jr, Wahl RC, Wen PH, Wood S (2011) From fragment screening to in vivo efficacy: optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). J Med Chem 54(16):5836–5857. doi: 10.1021/jm200544q CrossRefGoogle Scholar
  91. 91.
    Stachel SJ, Steele TG, Petrocchi A, Haugabook SJ, McGaughey G, Katharine Holloway M, Allison T, Munshi S, Zuck P, Colussi D, Tugasheva K, Wolfe A, Graham SL, Vacca JP (2012) Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency. Bioorg Med Chem Lett 22(1):240–244. doi: 10.1016/j.bmcl.2011.11.024 CrossRefGoogle Scholar
  92. 92.
    Huang Y, Strobel ED, Ho CY, Reynolds CH, Conway KA, Piesvaux JA, Brenneman DE, Yohrling GJ, Moore Arnold H, Rosenthal D, Alexander RS, Tounge BA, Mercken M, Vandermeeren M, Parker MH, Reitz AB, Baxter EW (2010) Macrocyclic BACE inhibitors: optimization of a micromolar hit to nanomolar leads. Bioorg Med Chem Lett 20(10):3158–3160. doi: 10.1016/j.bmcl.2010.03.097 CrossRefGoogle Scholar
  93. 93.
    Boy KM, Guernon JM, Wu Y-J, Zhang Y, Shi J, Zhai W, Zhu S, Gerritz SW, Toyn JH, Meredith JE, Barten DM, Burton CR, Albright CF, Good AC, Grace JE, Lentz KA, Olson RE, Macor JE, Thompson Iii LA (2015) Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE). Bioorg Med Chem Lett 25(22):5040–5047. doi: 10.1016/j.bmcl.2015.10.031 CrossRefGoogle Scholar
  94. 94.
    CoMentis. Safety study of CTS21166 to treat Alzheimer’s disease. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 28]. Available from: https://clinicaltrials.gov/show/NCT00621010
  95. 95.
    Koelsch G (2008) Beta-secretase inhibitor CTS-21166 reduces plasma Aβ40 in human subjects. In: Keystone symposium on Alzheimer’s disease, Keystone, Colorado, USA, 2008Google Scholar
  96. 96.
    Strobel G (2008) Keystone drug news: CoMentis BACE inhibitor debuts. Alzforum. http://www.alzforum.org/news/conference-coverage/keystone-drug-news-comentis-bace-inhibitor-debuts?id=1790. Accessed 25 July 2016
  97. 97.
    Eli Lilly and Company. A safety study of LY2811376 single doses in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 28]. Available from: https://clinicaltrials.gov/show/NCT00838084
  98. 98.
    May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, Stout SL, Timm DE, Smith Labell E, Gonzales CR, Nakano M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO, Cocke PJ, Greg Hall D, Friedrich S, Citron M, Audia JE (2011) Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci 31(46):16507–16516. doi: 10.1523/JNEUROSCI.3647-11.2011 CrossRefGoogle Scholar
  99. 99.
    LY2886721. Alzforum. Available via Biomedical Research Forum, LLC. http://www.alzforum.org/therapeutics/ly2886721. Accessed 29 Apr 2016
  100. 100.
    Eli Lilly and Company. A safety study of LY2886721 single doses in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01133405
  101. 101.
    Eli Lilly and Company. Multiple-ascending dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of LY2886721 in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01227252
  102. 102.
    Eli Lilly and Company. Disposition of 14C-LY2886721 following oral administration in healthy human subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01367262
  103. 103.
    Eli Lilly and Company. Single- and multiple-dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of LY2886721 in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01534273
  104. 104.
    Eli Lilly and Company. Assessment of safety, tolerability, and pharmacodynamic effects of LY2886721 in patients with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01561430
  105. 105.
    Eli Lilly and Company. A comparison study of capsule and orally disintegrating tablet and to determine the effect of food and water on the pharmacokinetics of LY2886721 in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01775904
  106. 106.
    Eli Lilly and Company (2013) Lilly voluntarily terminates phase II study for LY2886721, a β-secretase inhibitor, being investigated as a treatment for Alzheimer’s disease. https://investor.lilly.com/releasedetail.cfm?releaseid=771353
  107. 107.
    Landhuis E (2012) Wave of new BACE inhibitors heading to phase 2. Biomedical Research Forum, LLC. Available via Alzforum. http://www.alzforum.org/news/conference-coverage/wave-new-bace-inhibitors-heading-phase-2. Accessed 29 Apr 2016
  108. 108.
    Eisai Inc. A randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of E2609 in healthy subjects and an elderly cohort. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01294540
  109. 109.
    Lai R, Albala B, Kaplow JM, Aluri J, Yen M, Satlin A. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma β-amyloid levels after single dosing. Alzheimers Dement 8(4):P96. doi: 10.1016/j.jalz.2012.05.237
  110. 110.
    Eisai Inc. A randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of E2609 in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01511783
  111. 111.
    Albala B, Kaplow JM, Lai R, Matijevic M, Aluri J, Satlin A. CSF amyloid lowering in human volunteers after 14 days’ oral administration of the novel BACE1 inhibitor E2609. Alzheimers Dement 8(4):S743. doi: 10.1016/j.jalz.2013.08.023
  112. 112.
    Eisai Inc. A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of E2609 in subjects with mild cognitive impairment or mild dementia due to Alzheimer’s disease. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01600859
  113. 113.
    Eisai Inc. A randomized, open-label, 3-treatment crossover study to determine the bioavailability of E2609 tablets compared to capsules and the effect of food on absorption in healthy Caucasian male adults. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01716897
  114. 114.
    Eisai Inc. An open-label, single dose study to determine the metabolism and elimination or [14C]E2609 in healthy male subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT01975636
  115. 115.
    Eisai Inc. A 3-part, open-label, drug-drug interaction study of concomitant administration of E2609 with itraconazole, rifampin, digoxin, or donepezil. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT02055703
  116. 116.
    Eisai Inc. Study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of E2609 in healthy adult male Japanese and white subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT02207790
  117. 117.
    Eisai Inc. A randomized, double-blind, placebo and active-controlled, single-dose, 4-treatment crossover study to evaluate the effects of E2609 on QTc interval in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT02222324
  118. 118.
    Eisai Inc, Biogen. A placebo-controlled, double-blind, parallel-group, randomized, proof-of-concept, dose-finding study to evaluate safety, tolerability, and efficacy of E2609 in subjects with mild cognitive impairment due to Alzheimer’s disease (prodromal Alzheimer’s disease) and mild to moderate dementia due to Alzheimer’s disease. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 Apr 29]. Available from: https://clinicaltrials.gov/show/NCT02322021
  119. 119.
    Jeppsson F, Eketjall S, Janson J, Karlstrom S, Gustavsson S, Olsson LL, Radesater AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Falting J (2012) Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer’s disease. J Biol Chem 287(49):41245–41257. doi: 10.1074/jbc.M112.409110 CrossRefGoogle Scholar
  120. 120.
    AstraZeneca. A phase I, randomized, double-blind, placebo-controlled, parallel-group, single ascending dose study to assess the safety, tolerability, pharmacokinetics, and effect on biomarkers of AZD3839 including an open-label food effect group in healthy male and female volunteers of non-childbearing potential. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01348737
  121. 121.
    Quartino A, Huledal G, Sparve E, Luttgen M, Bueters T, Karlsson P, Olsson T, Paraskos J, Maltby J, Claeson-Bohnstedt K, Lee CM, Alexander R, Falting J, Paulsson B (2014) Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers. Clin Pharmacol Drug Dev 3(5):396–405. doi: 10.1002/cpdd.130 CrossRefGoogle Scholar
  122. 122.
    Jacobsen H, Ozmen L, Caruso A, Narquizian R, Hilpert H, Jacobsen B, Terwel D, Tanghe A, Bohrmann B (2014) Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. J Neurosci 34(35):11621–11630. doi: 10.1523/JNEUROSCI.1405-14.2014 CrossRefGoogle Scholar
  123. 123.
    Hoffmann-La Roche. A single-center, randomized, double-blind, single and multiple ascending dose, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (including the effect of food) and pharmacodynamics of RO5598887 following oral administration in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01461967
  124. 124.
    Hoffmann-La Roche. A single-center, randomized, investigator/subject-blind, single dose, placebo-controlled, parallel group study to investigate the pharmacodynamic and pharmacokinetic behavior or RO5508887 in plasma and cerebral spinal fluid following oral administration in healthy volunteers. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/ct2/show/NCT01592331?term=RO5508887&rank=2
  125. 125.
    Hoffmann-La Roche. A single-center, randomized, investigator/subject-blind, multiple ascending-dose, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of RO5508887 following oral administration in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01664143
  126. 126.
    Pfizer. A phase 1, randomized investigator-and-subject-blind, sponsor open, placebo controlled two-part study to characterize the pharmacokinetics and pharmacodynamics of single doses of PF-05297909 in healthy adult subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01462851
  127. 127.
    Bell J, O’Neill B, Brodney M, Hajos-Korcsok E, Lu Y, Riddell D, Ito K, Ueckert S, Nicholas T (2013) A novel BACE inhibitor (PF-05297909): a two-part adaptive design to evaluate safety, pharmacokinetics and pharmacodynamics for modifying beta-amyloid in a first-in-human study. Alzheimers Dement 9(4):287. doi: 10.1016/j.jalz.2013.05.578 CrossRefGoogle Scholar
  128. 128.
    High Point Pharmaceuticals LLC. A double-blind, randomized, placebo-controlled, phase I, multiple-dose study to evaluate the safety, tolerability, and pharmacokinetics of orally-administered HPP854 in subjects with mild cognitive impairment or a diagnosis of mild Alzheimer’s disease. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01482013
  129. 129.
    Forman M, Palcza J, Tseng J, Leempoels J, Ramael S, Han D, Jhee S, Ereshefsky L, Tanen M, Laterza O, Dockendorf M, Krishna G, Ma L, Wagner J, Troyer M (2012) The novel BACE inhibitor MK-8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single- and multiple-dose administration. Alzheimers Dement 8(4):P704. doi: 10.1016/j.jalz.2012.05.1900 CrossRefGoogle Scholar
  130. 130.
    Tseng J, Dockendorf M, Krishna G, Ma L, Palcza J, Leempoels J, Ramael S, Han D, Jhee S, Ereshefsky L, Wagner J, Troyer M, Forman M (2012) Safety and pharmacokinetics of the novel BACE inhibitor MK-8931 in healthy subjects following single- and multiple-dose administration. Alzheimers Dement 8(4 Suppl):P184–P185. doi: 10.1016/j.jalz.2012.05.500 CrossRefGoogle Scholar
  131. 131.
    Merck Sharp & Dohme Corp. A study to assess the safety, tolerability, and pharmacodynamics of MK-8931/SCH 900931 in patients With Alzheimer’s disease [phase 1b; protocol No. 010–00 (also known as P07820)]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01496170
  132. 132.
    Merck Sharp & Dohme Corp. An open-label, two-part, single-dose study to investigate the pharmacokinetics of MK-8931 in subjects With renal insufficiency (protocol No. MK-8931-009 [P08535]). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01537757
  133. 133.
    Merck Sharp & Dohme Corp. A randomized, placebo controlled, parallel-group, double blind efficacy and safety trial of MK-8931 with a long term double-blind extension in subjects with mild to moderate Alzheimer’s disease (protocol No. MK-8931-017-10) (also known as SCH 900931, P07738). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01739348
  134. 134.
    Merck (2013) Merck advances development of program for investigational Alzheimer’s disease therapy, MK-8931. http://www.mercknewsroom.com/news-release/prescription-medicine-news/merck-advances-development-program-investigational-alzheimer
  135. 135.
    Merck Sharp & Dohme Corp. A phase III, randomized, placebo-controlled, parallel-group, double-blind clinical trial to study the efficacy and safety of MK-8931 (SCH 900931) in subjects with amnestic mild cognitive impairment due to Alzheimer’s disease (prodromal AD). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/study/NCT01953601
  136. 136.
    AstraZeneca. A phase I, randomized, double-blind, placebo-controlled, single ascending dose study to assess the safety, tolerability, pharmacokinetics and effect on biomarkers of AZD3293 including an open-label food effect group in healthy male and non-fertile female volunteers. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01739647
  137. 137.
    AstraZeneca. A phase I, randomized, double-blind, placebo-controlled, two-part, multiple ascending dose study to assess the safety, tolerability, pharmacokinetics and effect on biomarkers of AZD3293 in plasma and cerebrospinal fluid in healthy male and non-fertile female elderly volunteers and in mild-to-moderate Alzheimer disease patients. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01795339
  138. 138.
    AstraZeneca. A phase I, single-center, open-label, 3-group, fixed-sequence study to assess the effect of itraconazole, a potent CYP3A4 inhibitor, or diltiazem, a moderate CYP3A4 inhibitor, on the pharmacokinetics of AZD3293 and the effects of AZD3293 on the pharmacokinetics of midazolam, a CYP3A4/CYP3A5 substrate, in healthy young male and female volunteers. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02010970
  139. 139.
    AstraZeneca. A phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study to assess the safety, tolerability, pharmacokinetics and effect on biomarkers of AZD3293 in healthy Japanese male and non-fertile female volunteers including elderly. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02005211
  140. 140.
    AstraZeneca, Parexel. A single-center, randomized, double-blinded, placebo-controlled, 4-way cross-over study to assess the effect of a single oral dose of AZD3293 administration on QTc interval compared to placebo, using open-label AVELOX (moxifloxacin) as a positive control, in healthy male subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02040987
  141. 141.
    AstraZeneca. A phase 1, open-label, randomized, single-dose, 3-period cross-over, relative bioavailability study to assess two solid formulations compared to an oral solution of AZD3293 in healthy male and non-fertile female subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02039180
  142. 142.
    Eli Lilly and Company, AstraZeneca. A bioequivalence and food effect study in healthy subjects administered 2 different tablet formulations of AZD3293. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02663128
  143. 143.
    AstraZeneca. A phase I, open-label, single-center study to assess the absorption, metabolism, and excretion after oral administration of [14C]-AZD3293 to healthy male subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02126514
  144. 144.
    Eli Lilly and Company, AstraZeneca. A study to characterize AZD3293 pharmacokinetics as a function of dosing duration and to determine the effect of AZD3293 on the pharmacokinetics of CYP3A substrates in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02406261
  145. 145.
    Eli Lilly and Company, AstraZeneca. Effect of AZD3293 on the pharmacokinetics of warfarin in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02540668
  146. 146.
    Eli Lilly and Company, AstraZeneca. Effect of AZD3293 on the pharmacokinetics of dabigatran in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02568397
  147. 147.
    AstraZeneca (2014) AstraZeneca and Lilly announce alliance to develop and commercialize BACE inhibitor AZD3293 for Alzheimer’s disease. https://www.astrazeneca.com/media-centre/press-releases/2014/astrazeneca-lilly-bace-inhibitor-azd3293-alzheimers-disease-16092014.html
  148. 148.
    Eli Lilly and Company, AstraZeneca. A 24-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy, safety, tolerability, biomarker, and pharmacokinetic study of AZD3293 in early Alzheimer’s disease (The AMARANTH Study). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02245737
  149. 149.
    Janssen Research & Development LLC. A double-blind, placebo-controlled, randomized, single-ascending dose study to investigate the safety, tolerability and pharmacokinetics of JNJ-54861911 in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01827982
  150. 150.
    Janssen Research & Development LLC. A double-blind, placebo-controlled, randomized, multiple-ascending dose study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-54861911 in healthy elderly subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01887535
  151. 151.
    Janssen Research & Development LLC. A randomized, open-label, 3-Way crossover study in healthy older male subjects to evaluate the bioavailability, food effect, safety and tolerability of a solid dosage formulation of JNJ-54861911. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02260700
  152. 152.
    Janssen Research & Development LLC. A double-blind, placebo-controlled, randomized, 4-week, multiple-dose, proof-of-mechanism study in subjects with prodromal Alzheimer’s disease investigating the effects of JNJ-54861911 on Aβ processing in CSF and plasma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT01978548
  153. 153.
    Janssen Pharmaceutical K.K. A double-blind, placebo-controlled, randomized, single-ascending dose study to investigate the safety, tolerability and pharmacokinetics of JNJ-54861911 in healthy Japanese male subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02180269
  154. 154.
    Janssen Pharmaceutical K.K. A double-blind, placebo-controlled, randomized, 4-Week, multiple-dose, proof of mechanism (POM) study in Japanese subjects asymptomatic at risk for Alzheimer dementia (ARAD) investigating the effects of JNJ-54861911 on Aβ Processing in cerebrospinal fluid (CSF) and plasma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02360657
  155. 155.
    Janssen Research & Development LLC. An open-label, fixed-sequence study to assess effects of clarithromycin on the single-dose pharmacokinetics of JNJ-54861911 in healthy male subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02197884
  156. 156.
    Janssen Research & Development LLC. An open-label, fixed-sequence study in healthy male subjects to assess the drug interaction potential of multiple-doses of JNJ-54861911 with a drug “cocktail” representative for CYP3A4, CYP2B6, CYP2C9, and CYP1A2 substrates. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02211079
  157. 157.
    Janssen Research & Development LLC. A phase 1, 2-panel, open-label, fixed-sequence study in healthy adult subjects to investigate the pharmacokinetic interaction between JNJ-54861911 and transporter substrates rosuvastatin and metformin. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02611518
  158. 158.
    Janssen Research & Development LLC. A randomized, double-blind, placebo- and positive-controlled, multiple-dose, four-way, cross-over study to evaluate the effects of repeated oral doses of JNJ-54861911 on electrocardiogram intervals in healthy subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02152332
  159. 159.
    Janssen Research & Development LLC. An open-label, randomized, three-period crossover study to evaluate the relative oral bioavailability and food effect of JNJ-54861911 tablet (1x25mg) after single dose administration in healthy elderly subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02355561
  160. 160.
    Janssen Research & Development LLC. A phase 2a randomized, double-blind, placebo-controlled, parallel-group, multi-center study investigating the safety and tolerability of JNJ-54861911 in subjects with early Alzheimer’s disease. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02260674
  161. 161.
    Janssen Research & Development LLC. A randomized, two-period, double-blind placebo-controlled and open-label, multicenter extension study to determine the long-term safety and tolerability of JNJ-54861911 in subjects in the early Alzheimer’s disease spectrum. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02406027
  162. 162.
    Janssen Research & Development LLC. A phase 2b/3 randomized, double-blind, placebo-controlled, parallel group, multicenter study investigating the efficacy and safety of JNJ-54861911 in subjects who are asymptomatic at risk for developing Alzheimer’s dementia. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02569398
  163. 163.
    Boehringer Ingelheim. Safety, tolerability, pharmacokinetics and pharmacodynamics of single rising oral doses of BI 1181181 in healthy male volunteers in a partially randomised, single-blind, placebo-controlled trial, and investigation of relative bioavailability and the effect of food on the pharmacokinetics of BI 1181181(open-label, randomised, three-way cross-over design). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02044406
  164. 164.
    Boehringer Ingelheim. Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 1181181 in young healthy male volunteers (randomised, double-blind, placebo-controlled within dose groups phase I trial). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02106247
  165. 165.
    Vitae Pharmaceuticals (2014) Positive top-line results achieved from two phase 1 clinical trials of BACE inhibitor BI1181181/VTP-37948 in Alzheimer’s disease. http://ir.vitaepharma.com/phoenix.zhtml?c=219654&p=irol-newsArticle&ID=1981037
  166. 166.
    Boehringer Ingelheim. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of BI 1181181 given orally q.d. for 10 days in young healthy male and elderly healthy male/female volunteers (randomized, double-blind, placebo controlled within dose groups phase I study). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02254161
  167. 167.
    Vitae Pharmaceuticals (2015) BACE inhibitor BI 1181181 voluntarily put on temporary clinical hold for safety evaluation. http://ir.vitaepharma.com/phoenix.zhtml?c=219654&p=irol-newsArticle&ID=2020814
  168. 168.
    Boehringer Ingelheim. A study to investigate the effects of BI 1181181 on the pharmacokinetics of midazolam, warfarin, omeprazole and digoxin in healthy male subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 02]. Available from: https://clinicaltrials.gov/show/NCT02345304
  169. 169.
    Novartis Pharmaceuticals. A randomized, double-blind, placebo-controlled, parallel-group study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple oral doses of CNP520 in healthy elderly subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 03]. Available from: https://clinicaltrials.gov/show/NCT02576639
  170. 170.
    Novartis Pharmaceuticals, Banner Alzheimer’s Institute, National Institute on Aging, Alzheimer’s Association, Amgen. A randomized, double-blind, placebo-controlled, two-cohort, parallel group study to evaluate the efficacy of CAD106 and CNP520 in participants at risk for the onset of clinical symptoms of Alzheimer’s disease. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [2016 May 03]. Available from: https://clinicaltrials.gov/show/NCT02565511

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Arun K. Ghosh
    • 1
    • 2
    Email author
  • Emilio L. Cárdenas
    • 1
  • Heather L. Osswald
    • 1
  1. 1.Department of ChemistryPurdue UniversityWest LafayetteUSA
  2. 2.Department of Medicinal ChemistryPurdue UniversityWest LafayetteUSA

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