Nonpeptide bace1 inhibitors: Design and synthesis

Aspartic Acid Proteases as Therapeutic Targets

Volumn 45, Issue , 2011, Pages 481-509

  Cole, Derek C ^a   Bursavich, Matthew G ^b  

^a Takeda San Diego Inc   (United States)

^b Myriad Pharmaceuticals   (United States)

Author keywords

Amyloid precursor protein; Aspartyl protease; BACE1 inhibitor; Cathepsin D; HIV protease; Hydrogen bonding interactions

Indexed keywords

EID: 85017332567     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527630943.ch17     Document Type: Chapter

References (143)

1. www.alz.org/alzheimers_ disease_Alzheimer'statistics.asp.
2. Ferri, C.P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K., Hasegawa, K., Hendrie, H., Huang, Y., Jorm, A., Mathers, C., Menezes, P.R., Rimmer, E., and Scazufca, M. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet, 366, 2112-2117.
3. Selkoe, D.J. (1991) Alzheimer's disease in the beginning. Nature, 354, 432-433.
4. Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 297, 353-356.
5. Li, Y.M., Xu, M., Lai, M.T., Huang, Q., Castro, J.L., DiMuzio-Mower, J., Harrison, T., Lellis, C., Nadin, A., Neduvelil, J.G., Register, R.B., Sardana, M.K., Shearman, M.S., Smith, A.L., Shi, X.P., Yin, K.C., Shafer, J.A., and Gardell, S.J. (2000) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature, 405, 689-694.
6. Sinha, S. and Lieberburg, I. (1999) Cellular mechanisms of beta-amyloid production and secretion. Proceedings of the National Academy of Sciences of the United States of America, 96, 11049-11053.
7. Wolfe, M.S., Xia, W., Ostaszewski, B.L., Diehl, T.S., Kimberly, W.T., and Selkoe, D.J. (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gammasecretase activity. Nature, 398, 513-517.
8. Beher, D. and Graham, S.L. (2005) Protease inhibitors as potential diseasemodifying therapeutics for Alzheimer's disease. Expert Opinion on Investigational Drugs, 14, 1385-1409.
9. Durham, T.B. and Shepherd, T.A. (2006) Progress toward the discovery and development of efficacious BACE inhibitors. Current Opinion in Drug Discovery & Development, 9, 776-791.
10. Melnikova, I. (2007) Therapies for Alzheimer's disease. Nature Reviews. Drug Discovery, 6, 341-342.
11. Marjaux, E., Hartmann, D., and De Strooper, B. (2004) Presenilins in memory, Alzheimer's disease, and therapy. Neuron, 42, 189-192.
12. Wolfe, M.S. (2006) The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry, 45, 7931-7939.
13. Fleisher, A.S., Raman, R., Siemers, E.R., Becerra, L., Clark, C.M., Dean, R.A., Farlow, M.R., Galvin, J.E., Peskind, E.R., Quinn, J.F., Sherzai, A., Sowell, B.B., Aisen, P.S., and Thal, L.J. (2008) Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Archives of Neurology, 65, 1031-1038.
14. Siemers, E.R., Dean, R.A., Friedrich, S., Ferguson-Sells, L., Gonzales, C., Farlow, M.R., andMay, P.C. (2007) Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clinical Neuropharmacology, 30, 317-325.
15. Barten, D.M.,Guss, V.L., Corsa, J.A., Loo, A., Hansel, S.B., Zheng, M., Munoz, B., Srinivasan, K.,Wang, B., Robertson, B.J., Polson, C.T., Wang, J., Roberts, S.B., Hendrick, J.P., Anderson, J.J., Loy, J.K., Denton, R., Verdoorn, T.A., Smith, D.W., and Felsenstein, K.M. (2005) Dynamics of beta-amyloid reductions in brain, cerebrospinal fluid, and plasma of betaamyloid precursor protein transgenic mice treated with a gamma-secretase inhibitor. The Journal of Pharmacology and Experimental Therapeutics, 312, 635-643.
16. Mayer, S.C., Kreft, A.F., Harrison, B., Abou-Gharbia, M., Antane, M., Aschmies, S., Atchison, K., Chlenov, M., Cole, D.C., Comery, T., Diamantidis, G., Ellingboe, J., Fan, K., Galante, R., Gonzales, C., Ho, D.M., Hoke, M.E., Hu, Y., Huryn, D., Jain, U., Jin, M., Kremer, K., Kubrak, D., Lin, M., Lu, P., Magolda, R., Martone, R., Moore, W., Oganesian, A., Pangalos, M.N., Porte, A., Reinhart, P., Resnick, L., Riddell, D.R., Sonnenberg-Reines, J., Stock, J.R., Sun, S.C., Wagner, E., Wang, T., Woller, K., Xu, Z., Zaleska, M.M., Zeldis, J., Zhang, M., Zhou, H., and Jacobsen, J.S. (2008) Discovery of begacestat, a Notch-1-sparing gammasecretase inhibitor for the treatment of Alzheimer's disease. Journal of Medicinal Chemistry, 51 7348-7351.
17. Macor, J.E., Albright, C.F.,Meredith, J.E., Zaczek, R.C., Barten, D.M., Toyn, J.H., Slemmon, R., Lentz, K., Wang, J.-S., Denton, R., Pilcher, G.,Wang, O.,Gu, H., Dockens, R., Berman, R., Tong, G., Bronson, J.J., Parker, M.F., Mate, R.A., McElhone, K., Starrett, J.E., Jr., Gillman, K.W., and Olson, R.E. (2009) Discovery of BMS-708163: a potent and selective gamma-secretase inhibitor which lowers CSF beta-amyloid in humans. ACS National Meeting, Salt Lake City, UT, United States, March 22-26, MEDI-027.
18. Imbimbo, B.P. (2008) Alzheimer's disease: c-secretase inhibitors. Drug Discovery Today: Therapeutic Strategies, 5, 169-175.
19. ELAN Annual Report 2008.
20. Vassar, R. (2002) Beta-secretase (BACE) as a drug target for Alzheimer's disease. Advanced Drug Delivery Reviews, 54, 1589-1602.
21. Luo, Y., Bolon, B., Kahn, S., Bennett, B.D., Babu-Khan, S., Denis, P., Fan, W., Kha, H., Zhang, J., Gong, Y., Martin, L., Louis, J.C., Yan, Q., Richards, W.G., Citron, M., and Vassar, R. (2001) Mice deficient in BACE1, the Alzheimer's betasecretase, have normal phenotype and abolished beta-amyloid generation. Nature Neuroscience, 4, 231-232.
22. Cai, H.,Wang, Y., McCarthy, D.,Wen, H., Borchelt, D.R., Price, D.L., and Wong, P.C. (2001) BACE1 is the major beta-secretase for generation of Ab peptides by neurons. Nature Neuroscience, 4, 233-234.
23. Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A.Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., and Selkoe, D.J. (1992) Mutation of the betaamyloid precursor protein in familial Alzheimer's disease increases betaprotein production. Nature, 360, 672-674.
24. Farzan, M., Schnitzler, C.E., Vasilieva, N., Leung, D., and Choe, H. (2000) BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proceedings of the National Academy of Sciences of the United States of America, 97, 9712-9717.
25. Bursavich, M.G. and Rich, D.H. (2002) Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. Journal of Medicinal Chemistry, 45, 541-558.
26. Fruton, J.S. (1976) The mechanism of the catalytic action of pepsin and related acid proteinases. Advances in Enzymology and Related Areas of Molecular Biology, 44, 1-36.
27. James, M.N., Sielecki, A.R., Hayakawa, K., and Gelb, M.H. (1992) Crystallographic analysis of transition state mimics bound to penicillopepsin: difluorostatine-and difluorostatonecontaining peptides. Biochemistry, 31, 3872-3886.
28. Pearl, L. and Blundell,T. (1984) The active site of aspartic proteinases. FEBS Letters, 174, 96-101.
29. Suguna, K., Padlan, E.A., Smith, C.W., Carlson, W.D., and Davies, D.R. (1987) Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action. Proceedings of the National Academy of Sciences of the United States of America, 84, 7009-7013.
30. Cumming, J.N., Iserloh, U., and Kennedy, M.E. (2004) Design and development of BACE-1 inhibitors. Current Opinion in Drug Discovery & Development, 7, 536-556.
31. Hong, L., Koelsch, G., Lin, X., Wu, S., Terzyan, S., Ghosh, A.K., Zhang, X.C., and Tang, J. (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science, 290, 150-153.
32. Coburn, C.A., Stachel, S.J., Li, Y.-M., Rush, D.M., Steele, T.G., Chen-Dodson, E., Holloway, M.K., Xu, M., Huang, Q., Lai, M.-T., DiMuzio, J., Crouthamel, M.-C., Shi, X.-P., Sardana, V., Chen, Z., Munshi, S., Kuo, L., Makara, G.M., Annis, D.A., Tadikonda, P.K., Nash, H.M., and Vacca, J.P. (2004) Identification of a small molecule nonpeptide active site b-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases. Journal of Medicinal Chemistry, 47, 6117-6119.
33. Thompson, L., Boy, K., Shi, J., and Macor, J. (2006) Novel isophthalates as beta-secretase inhibitors. US Patent 20060229309A1.
34. Ghosh, A.K., Kumaragurubaran, N., Hong, L., Kulkarni, S., Xu, X., Miller, H.B., Reddy, D.S., Weerasena, V., Turner, R., Chang, W., Koelsch, G., and Tang, J. (2008) Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorganic & Medicinal Chemistry Letters, 18, 1031-1036.
35. Ghosh, A.K., Kumaragurubaran, N., Hong, L., Kulkarni, S.S., Xu, X., Chang, W., Weerasena, V., Turner, R., Koelsch, G., Bilcer, G., and Tang, J. (2007) Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. Journal of Medicinal Chemistry, 50, 2399-2407.
36. http://www.athenagen.com.
37. Cole, D.C., Manas, E.S., Stock, J.R., Condon, J.S., Jennings, L.D., Aulabaugh, A., Chopra, R., Cowling, R., Ellingboe, J.W., Fan, K.Y., Harrison, B.L., Hu, Y., Jacobsen, S., Jin, G., Lin, L., Lovering, F.E., Malamas, M.S., Stahl, M.L., Strand, J., Sukhdeo, M.N., Svenson, K., Turner, M.J., Wagner, E., Wu, J., Zhou, P., and Bard, J. (2006) Acylguanidines as small-molecule b-secretase inhibitors. Journal of Medicinal Chemistry, 49, 6158-6161.
38. Cole, D., Manas, E., Jennings, L., Lovering, F., Stock, J., Moore, W., Ellingboe, J., Condon, J., Sukhdeo, M., Zhou, P., Wu, J., and Morris, K. (2006) Azolylacylguanidines as beta-secretase inhibitors. US Patent 20060183790A1.
39. Jennings, L.D., Cole, D.C., Stock, J.R., Sukhdeo, M.N., Ellingboe, J.W., Cowling, R., Jin, G., Manas, E.S., Fan, K.Y., Malamas, M.S., Harrison, B.L., Jacobsen, S., Chopra, R., Lohse, P.A., Moore, W.J., O'Donnell, M.-M., Hu, Y., Robichaud, A.J., Turner, M.J.,Wagner, E., and Bard, J. (2008) Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S01 substrate binding pocket. Bioorganic & Medicinal Chemistry Letters, 18, 767-771.
40. Fobare, W. and Solvibile, W. (2006) Substituted thienyl and furyl acylguanidines and methods of their use as beta-secretase modulators. US Patent 20060183792A1.
41. Hu, B. (2006) Terphenyl guanidines as beta-secretase inhibitors. US Patent 20060183943A1.
42. Malamas, M., Fobare, W., Solvibile, W., Lovering, F., Condon, J., and Robichaud, A. (2006) Amino-pyridines as inhibitors of beta-secretase. US Patent 20060173049A1.
43. Berg, S. and Kolmodin, K. (2007) Thiazol-guanidine derivatives useful as a b-related pathologies. WO2007120096A1.
44. Gerritz, S., Shi, S., and Zhu, S. (2006) Aminoacetamide acyl guanidines as beta-secretase inhibitors. US Patent 20060287287A1.
45. Wu, Y.J., Gerritz, S., Shi, S., and Zhu, S. (2007) Oxime-containing acyl guanidines as beta-secretase inhibitors. US Patent 20070232581A1.
46. Thompson, L.A., Shi, J., Zusi, F.C., Dee, M.F., and Macor, J.E. (2007) Indole acetic acid acyl guanidines as betasecretase inhibitors. US Patent 20070049589A1.
47. Shi, S., Gerritz, S., and Zhu, S. (2008) Macrocyclic acyl guanidines as betasecretase inhibitors. US Patent 20080262055A1.
48. Wu, Y.-J., Gerritz, S., Shi, S., and Zhu, S. (2008) Oxime-containing macrocyclic acyl guanidines as b-secretase inhibitors. US Patent 20080139523A1.
49. Mjalli, A., Jones, D., Gohimukkula, D., Huang, G., Zhu, J., Rao, M., Andrews, R., and Ren, T. (2006) Benzazole derivatives, compositions, and methods of use as beta-secretase inhibitors. US Patent 20060223849A1.
50. Malamas, M.S., Erdei, J.J.,Gunawan, I.S., Zhou, P., Yan, Y., and Quagliato, D.A. (2005) Preparation of amino-5,5-diphenylimidazolone derivatives for inhibition of beta-secretase and treatment of b-amyloid-related diseases. US Patent 20050282825.
51. Nowak, P., Aulabaugh, A., Chen, J., Cole, D.C., Chopra, R., Cowling, R., Dar, M., Ellingboe, J.W., Fan, K.Y.,Hu, B., Jacobsen, S., Jani, M., Jin, G., Lo, M.-C., Malamas, M.S.,Manas, E.S., Narasimhan, R., Robichaud, A., Sabus, C., Stock, J.R., Tischler, M., Turner, J.,Wagner, E., Zhou, P., and Bard, J. (2007) Hit-to-lead optimization of aminohydantoins as b-secretase inhibitors. ACS National Meeting, Chicago, IL, United States, March 25-29, MEDI-307.
52. Malamas, M.S.,Gunawan, I.S., Erdei, J.J., Nowak, P.W., Stock, J.R., and Yan, Y. (2007) Cycloalkyl amino-hydantoin compounds and use thereof for b-secretase modulation and treatment of diseases with b-amyloid deposits and neurofibrillary tangles. US Patent 20070027199.
53. Malamas, M.S., Zhou, P., Fobare, W.F., Solvibile,W.R., Gunawan, I.S., Erdei, J.J., Yan, Y., Andrae, P.M., and Quagliato, D.A. (2007) Amino-5-(5-membered) hetero-arylimidazolone compounds and the use thereof for beta-secretase modulation. US Patent 20070004786.
54. Zhou, P., Malamas, M.S., Li, Y., Robichaud, A.J., and Quagliato, D.A. (2007) Amino-5-(6-membered) heteroarylimidazolone compounds and the use thereof for beta-secretase modulation. US Patent 20070004730.
55. Malamas, M., Erdei, J., Gunawan, I., Zhou, P., Yan, Y., and Quagliato, D. (2005) Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase. US Patent 20050282825A1.
56. Malamas, M.S., Erdei, J.J., Fobare, W.F., Quagliato, D.A., Antane, S.A., and Robichaud, A.J. (2007) Amino-5-[4-(difluoromehtoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase. US Patent 20070072925A1.
57. Malamas, M.S., Robichaud, A.J., Porte, A.M., Morris, K.M., Solvibile, W.R., and Kim, J.-I. (2009) Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of b-secretase. US Patent 20090048320A1.
58. Zhou, P., Bernotas, R.C., Li, Y., Nowak, P.W., Cole, D.C., Manas, E.S., Fan, Y., and Yan, Y. (2007) 2-Amino-5-piperidinylimidazolone compounds and use thereof for beta-secretase modulation. US Patent 20070191431A1.
59. Malamas, M.S., Robichaud, A.J., Porte, A.M., Solvibile, W.R., Morris, K.M., Antane, S.A., Kim, J.-I., and McDevitt, R.E. (2009) Amino-5-[substituted-4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds as b-secretase inhibitors. US Patent 20090042964A1.
60. Berg, S., Burrows, J., Chessari, G., Congreve, M.S., Hedstrom, J., Hellberg, S., Hogdin, K., Kihlstrom, J., Kolmodin, K., Lindstrom, J., Murray, C., and Patel, S. (2008) Novel 2-aminoimidazole-4-one compounds and their use in the manufacture of a medicament to be used in the treatment of cognitive impairment, Alzheimer's disease, neurodegeneration and dementia. US Patent 20080293718A1.
61. Berg, S., Holenz, J., Karlstrom, S., Kihlstrom, J., Lindstrom, J., and Rakos, L., (2008) New compounds 617. US Patent 20080176862A1.
62. Berg, S., Karlstrom, S., Kolmodin, K., Lindstrom, J., Nystrom, J.-E., Sehgelmeble, F., and Soderman, P. (2008) Compounds 620. US Patent 20080161269A1.
63. Burrows, J.N., Hellberg, S., Hogdin, K., Karlstrom, S., Kolmodin, K., Lindstrom, J., and Slivo, C. (2008) New compounds 835. US Patent 20080287460A1.
64. Berg, S., Hallberg, J., Hogdin, K., Karlstrom, S., Kers, A., Plobeck, N., and Rakos, L.,Novel 2-amino-5, 5-diaryl-imidazol-4-ones. WO2008076044A1.
65. 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., and Tadesse, D. (2006) Preparation of imidazolidin-2-imines and their analogs as aspartyl protease inhibitors for treating various diseases. US Patent 20060111370.
66. Iserloh, U., Zhu, Z., Stamford, A., and Voigt, J. (2006) Macrocyclic heterocyclic aspartyl protease inhibitors. US Patent 20060281729A1.
67. Andreini, M., Gabellieri, E., Guba, W., Marconi, G., Narquizian, R., Power, E., Travagli, M., Woltering, T., and Wostl, W. (2009) 4,5-Dihydro-oxazol-2-yl amine derivatives. US Patent 20090209529A1.
68. Murray, C.W., Callaghan, O., Chessari, G., Cleasby, A., Congreve, M., Frederickson, M., Hartshorn, M.J., McMenamin, R., Patel, S., and Wallis, N. (2007) Application of fragment screening by X-ray crystallography to b-secretase. Journal of Medicinal Chemistry, 50, 1116-1123.
69. Congreve, M., Aharony, D., Albert, J., Callaghan, O., Campbell, J., Carr, R.A.E., Chessari, G., Cowan, S., Edwards, P.D., Frederickson, M., McMenamin, R., Murray, C.W., Patel, S., and Wallis, N. (2007) Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of b-secretase. Journal of Medicinal Chemistry, 50, 1124-1132.
70. Albert, J.S., Edwards, P.D., Andisik, D., Campbell, J.B., Carr, R., Chessari, G., Congreve, M.S., Koether, G.M., Mauger, R.C.,Murray, C.W., Patel, S., and Sylvester, M.A. (2007) Fragment based lead generation approaches for inhibitors of beta-secretase: development of a novel series of dihydroisocytosine-based inhibitors. ACS National Meeting, Chicago, IL, United States,March 25-29, MEDI-310.
71. Albert, J.S., Edwards, P.D., Andisik, D., Campbell, J.B., Congreve, M.S., Carr, R., Chessari, G., Edfeldt, F., Folmer, R.H.A., Koether, G.M., Kolmodin, K., Murray, C.W., Olsson, L.-L., Patel, S., and DeBeer, T. (2007) Fragment based lead generation approaches for inhibitors of beta-secretase: development of a novel series of isocytosine-based inhibitors. ACS National Meeting, Chicago, IL, United States,March 25-29, MEDI-311.
72. Edwards, P.D. (2007) Fragment screening and its application to drug design: the discovery of low molecular weight, non-peptidic, nanomolar inhibitors of beta-secretase. ACS National Meeting, Chicago, IL, United States, March 25-29, MEDI-002.
73. 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., and Throner, S. (2006) Preparation of substituted 2-aminopyrimidin-4-ones for treating or preventing Ab-related pathologies. WO2006041404.
74. Albert, J.S., Callaghan, O., Campbell, J., Carr, R.A.E., Chessari, G., Cowan, S., Congreve, M.S., Edwards, P., Frederickson, M., Murray, C.W., and Patel, S. (2008) Substituted aminopyridines and uses thereof. US Patent 20080287399A1.
75. Albert, J., Andisik, D., Edwards, P., and Sylvester, M. (2008) Novel 2-aminopyrimidinone derivatives and their use. US Patent 20080255164A1.
76. Albert, J., Chessari, G., and Edwards, P. (2008) Novel 2-aminopyrimidine or 2-aminiopyridinone derivatives and their use. US Patent 20080255167A1.
77. Albert, J., Edwards, P., and Empfield, J. (2008) Novel 2-aminopyrimidinone or 2-aminopyridinone derivatives and their use. US Patent 20080318985A1.
78. McKittrick, B., Zhu, Z., Stamford, A., and Smith, E. (2007) Preparation and use of compounds as aspartyl protease inhibitors. US Patent 20070010667A1.
79. Kobayashi, N., Ueda, K., Itoh, N., Suzuki, S., Sakaguchi, G., Kato, A., Yukimasa, A., Hori, A., Koriyama, Y., Haraguchi, H., Yasui, K., and Kanda, Y. (2009) Aminodihydrothiazine derivatives. US Patent 20090082560A1.
80. Stachel, S.J., Coburn, C.A., Rush, D., Jones, K.L.G., Zhu, H., Rajapakse, H., Graham, S.L., Simon, A., Holloway, M.K., Allison, T.J., Munshi, S.K., Espeseth, A.S., Zuck, P., Colussi, D., Wolfe, A., Pietrak, B.L., Lai, M.-T., and Vacca, J.P. (2009) Discovery of aminoheterocycles as a novel betasecretase inhibitor class: pH dependence on binding activity part 1. Bioorganic & Medicinal Chemistry Letters, 19, 2977-2980.
81. Hills, I.D., Holloway, M.K., de Leon, P., Nomland, A., Zhu, H., Rajapakse, H., Allison, T.J., Munshi, S.K., Colussi, D., Pietrak, B.L., Toolan, D.,Haugabook, S.J., Graham, S.L., and Stachel, S.J. (2009) A conformational constraint improves a beta-secretase inhibitor but for an unexpected reason. Bioorganic & Medicinal Chemistry Letters, 19, 4993-4995.
82. Coburn, C.A., Espeseth, A.S., Stachel, S.J., Olsen, D.B., Hazuda, D.J., and Holloway, M.K. (2007) 2-Aminothiazole compounds useful as aspartyl protease inhibitors. US Patent 20070203147A1.
83. Coburn, C.A., Holloway, M.K., and Stachel, S.J. (2008) 2-Aminopyridine compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease. US Patent 20080161363A1.
84. Malamas, M.S., Erdei, J.J.,Gunawan, I.S., Barnes, K.D., Johnson, M.R., and Hui, Y. (2005) Preparation of diphenylimidazopyrimidine and -imidazole amines as selective inhibitors of b-secretase for use against Alzheimer's disease and other disorders. US Patent 20050282826.
85. Malamas, M.S., Barnes, K.D., and Johnson, M.R. (2008) Imidazole amines as inhibitors of beta-secretase. US Patent 20080051390A1.
86. Malamas, M., Erdei, J., Gunawan, I., Nowak, P., and Harrison, B. (2006) Amino-imidazolones for the inhibition of beta-secretase. US Patent 20060160828A1.
87. Malamas, M.S., Erdei, J., Gunawan, I., Barnes, K., Johnson, M., Hui, Y., Turner, J., Hu, Y., Wagner, E., Fan, K., Olland, A., Bard, J., and Robichaud, A.J. (2009) Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors. Journal ofMedicinal Chemistry, 52, 6314-6323.
88. Berg, S., Holenz, J., Hogdin, K., Kolmodin, K., Plobeck, N., Rotticci, D., and Sehgelmeble, F. (2007) New Compounds 319. US Patent 20070299087A1.
89. Berg, S., Holenz, J., Hogdin, K., Kihlstrom, J., Kolmodin, K., Lindstrom, J., Plobeck, N., Rotticci, D., Sehgelmeble, F., and Wirstam, M. (2008) New Compounds 318. US Patent 20080058349A1.
90. Berg, S., Hogdin, K., Kihlstrom, J., Plobeck, N., Sehgelmeble, F., and Wirstam, M. (2008) New compounds 317. US Patent 20080051420A1.
91. Berg, S., Holenz, J., Hogdin, K., Kolmodin, K., Plobeck, N., Rotticci, D., Sehgelmeble, F., and Wirstam, M. (2008) New compounds 320. US Patent 20080214577A1.
92. Arnold, J., Edwards, P., Sylvester, M., Berg, S., Holenz, J., Kers, A., Kolmodin, K., Rakos, L., Ohberg, L., Didier, R., Chessari, G., Congreve, M., Murray, C., and Patel, S. (2008) New compounds 391. US Patent 20080171771A1.
93. Holenz, J., Kers, A., Kolmodin, K., Rotticci, D., Rakos, L., and Hellberg, S. (2009) Aryl and heteroaryl substituted isoindole derivatives as BACE inhibitors. WO2009005471A1.
94. Holenz, J., Kers, A., Kolmodin, K., Rotticci, D., Ohberg, L., and Hellberg, S. (2009) Aryl and heteroaryl substituted isoindole derivatives as BACE inhibitors. WO2009005470A1.
95. Chessari, G., Congreve, M.S., Holenz, J., Murray, C., Patel, S., Rakos, L., and Rotticci, D. (2008) New compounds 834. US Patent 20080287462A1.
96. Albert, J., Chessari, G., Congreve, M.S., Edwards, P., Murray, C., Patel, S., and Sylvester, M. (2008) Novel 2-aminoheterocycles useful in the treatment of Ab-related pathologies. US Patent 20080293709A1.
97. Stamford, A., Li, G., Greenlee, W., Zhu, Z., McKittrick, B., Mazzola, R., Huang, Y. (2008) Guo, T., Le, T.X.H., Qian, G., and Shao, Y.,Preparation and use of compounds as protease inhibitors. US Patent 20080176868A1.
98. Bishoff, F.P., Bracken, M., Pieters, S.M.A., Mercken, M.H., De Winter, H.L.J., and Berthelot, D.J.-C. (2006) Novel 2-aminoquinazoline derivatives, their preparation and use as inhibitors of b-secretase for treating Alzheimer's disease and related disorders. WO2006024932.
99. Baxter, E., Bischoff, F.P., Boyd, R., Braeken, M., Coats, S., Huang, Y., Jordan, A., Luo, C., Mercken, M.H., Reynolds, C.H., Ross, T.M., Tounge, B.A., Schulz, M., De Winte, H.L.J., Pieters, S.M.A., and Reitz, A.B. (2008) Novel 2-aminoquinazoline derivatives, their preparation and use as inhibitors of b-secretase for treating Alzheimer's disease and related disorders. WO2006017836.
100. Baxter, E., Boyd, R., Coats, S., Jordan, A., Reitz, A., Reynolds, C.H., Scott, M., Schulz, M., and De Winter, H.L.J. (2006) Novel 2-aminoquinazoline derivatives, their preparation and use as inhibitors of b-secretase for treating Alzheimer's disease and related disorders. WO2006017844.
101. Baxter, E.W., Reitz, A.B., and Crieghton, C.J. (2007) 2-Amino-3,4-dihydro-quinoline derivatives useful as inhibitors of b-secretase (BACE). US Patent 20070232642A1.
102. Baxter, E.E., Creighton, C.J., Huang, Y., Luo, C., Parker, M.H., Reitz, A.B., Reynolds, C.H., Ross, T.M., Strobel, E., and Tounge, B.A. (2007) Novel 2-amino-3, 4-dihydro-pyrido[3,4-d]pyrimidine derivatives useful as inhibitors of b-secretase (BACE). US Patent 20070259898A1.
103. Baxter, E.W., Reitz, A.B., Parker, M.H., Huang, Y., Ho, C.Y., Strobel, E.D., and Reynolds, C.H. (2007) Macrocycle derivatives useful as inhibitors of b-secretase (BACE). US Patent 20070232630A1.
104. Fuchs, K., Dorner-Ciossek, C., Handschuh, S.,Heine, N., Hoerer, S., and Klinder, K. (2009) Substituted aminoquinazolinones, medicaments comprising said compound, their use and their method of manufacture. WO2009092566A1.
105. Marki, H.P., Binggeli, A., Bittner, B., Bohner-Lang, V., Breu, V., Bur, D., Coassolo, P., Clozel, J.P., D'Arcy, A., Doebeli, H., Fischli, W., Funk, C., Foricher, J., Giller, T., Gruninger, F., Guenzi, A., Guller, R., Hartung, T., Hirth, G., Jenny, C., Kansy, M., Klinkhammer, U., Lave, T., Lohri, B., Luft, F.C., Mervaala, E.M., Muller, D.N., Muller, M., Montavon, F., Oefner, C., Qiu, C., Reichel, A., Sanwald-Ducray, P., Scalone, M., Schleimer, M., Schmid, R., Stadler, H., Treiber, A., Valdenaire, O., Vieira, E., Waldmeier, P., Wiegand-Chou, R., Wilhelm, M., Wostl, W., Zell, M., and Zell, R. (2001) Piperidine renin inhibitors: from leads to drug candidates. Farmaco, 56, 21-27.
106. Vieira, E., Binggeli, A., Breu, V., Bur, D., Fischli, W., Guller, R., Hirth, G., Marki, H.P., Muller, M., Oefner, C., Scalone, M., Stadler, H., Wilhelm, M., and Wostl, W. (1999) Substituted piperidines: highly potent renin inhibitors due to induced fit adaptation of the active site. Bioorganic & Medicinal Chemistry Letters, 9, 1397-1402.
107. Oefner, C., Binggeli, A., Breu, V., Bur, D., Clozel, J.P., D'Arcy, A., Dorn, A., Fischli, W., Gruninger, F., Guller, R., Hirth, G., Marki, H.P., Mathews, S., Muller, M., Ridley, R.G., Stadler, H., Vieira, E., Wilhelm, M., Winkler, F.K., and Wostl, W. (1999) Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases? Chemistry & Biology, 6, 127-131.
108. Bursavich, M.G., West, C.W., and Rich, D.H. (2001) From peptides to non-peptide peptidomimetics: design and synthesis of new piperidine inhibitors of aspartic peptidases. Organic Letters, 3, 2317-2320.
109. Moon, J.B., Pulley, S.R., Rich, D.H., Brown, D.L., Jagodzinska, B., John, V., and Jacobs, J. (2008) 3,4-disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines. US Patent 7338965B2.
110. Herold, P., Mah, R., Stutz, S., Stojanovic, A., Tschinke, V., Jotterand, N., and Schumacher, C. (2006) Organic compounds. EP1707202A1.
111. Herold, P., Mah, R., Stutz, S., Stojanovic, A., Tschinke,V.,Marti, C., and Schumacher, C. (2006) Piperazine derivates for the inhibition of betasecretase, cathepsin D, plasmepsin ll and HIV protease and for the treatment of malaria, Alzeheimer and AIDS. EP1707206A1.
112. Herold, P., Mah, R., Stutz, S., Tschinke, V., Schumacher, C., Stojanovic, A., Jotterand, N., and Behnke, D. (2007) 3,4,5-Substituted piperidines as therapeutic compounds. US Patent 20070167433A1.
113. Herold, P., Mah, R., Tschinke, V., Stojanovic, A., Behnke, D., Marti, C., Stutz, S., and Jelakovic, S. (2008) Substituted piperidines as inhibitors of beta-secretase, cathepsin D, plasmepsin II and/or HIV protease. EP1958634A2.
114. Stachel, S.J., Steele, T., and Petrocchi, A. (2009) 3,4-Substituted pyrrolidine b-secretase inhibitors for the treatment of Alzheimer's disease. WO2009078932A1.
115. Bhisetti, G.R., Saunders, J.O., Murcko, M.A., Lepre, C.A., Britt, S.D., Come, J.H., Deninger, D.D., and Wang, T. (2002) Preparation of b-carbolines and other inhibitors of BACE-1 aspartic proteinase useful against Alzheimer's and other BACEmediated diseases. WO2002088101.
116. Garino, C., Pietrancosta, N., Laras, Y., Moret, V., Rolland, A., Quelever, G., and Kraus, J.L. (2006) BACE-1 inhibitory activities of new substituted phenylpiperazine coupled to various heterocycles: chromene, coumarin and quinoline. Bioorganic & Medicinal Chemistry Letters, 16, 1995-1999.
117. Garino, C., Tomita, T., Pietrancosta, N., Laras, Y., Rosas, R., Herbette, G., Maigret, B., Quelever, G., Iwatsubo, T., and Kraus, J.L. (2006) Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human beta-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays. Journal of Medicinal Chemistry, 49, 4275-4285.
118. Barrow, J.C., Stauffer, S.R., Rittle, K.E., Ngo, P.L., Yang, Z., Selnick, H.G., Graham, S.L., Munshi, S., McGaughey, G.B., Holloway, M.K., Simon, A.J., Price, E.A., Sankaranarayanan, S., Colussi, D., Tugusheva, K., Lai, M.-T., Espeseth, A.S., Xu, M., Huang, Q.,Wolfe, A., Pietrak, B., Zuck, P., Levorse, D.A., Hazuda, D., and Vacca, J.P. (2008) Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase. Journal of Medicinal Chemistry, 51 6259-6262.
119. Coburn, C., Egbertson, M., Graham, S., McGaughey, G., Stauffer, S., Rajapakse, H., Nantermet, P., Stachel, S., Yang, W., Lu, W., and Fahr, B. (2007) Spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease. US Patent 20070021454A1.
120. Barrow, J.C., Coburn, C.A., Egbertson, M.S., McGaughey, G.B., McWherter, M.A., Neilson, L.A., Rittle, K.E., Selnick, H.G., Stauffer, S.R., Yang, Z.Q., Yang,W., Lu,W., and Fahr, B. (2007) Spiropiperidine compounds useful as beta-secretase inhibitors for the treatment of Alzheimer? s disease. US Patent 20070197571A1.
121. Stauffer, S.R., Hills, I.D., and Nomland, A. (2008) Spiropiperidine b-secretase inhibitors for the treatment of Alzheimer's disease. WO2008054698A2.
122. Egbertson, M.S., Stauffer, S.R., Coburn, C.A., Barrow, J.C., Yang, W., Lu, W., Fahr, B., Neilson, L.A., and Wai, J.M. (2008) Spiropiperidine b-secretase inhibitors for the treatment of Alzheimer's Disease. WO2008030412A2.
123. Stauffer, S.R. and Graham, S.L. (2008) Bicyclic spiorpiperidine b-secretase inhibitors for the treatment of Alzheimer's disease. WO2008085509A1.
124. Nantermet, P.G., Holloway, M.K., Moore, K.P., and Stauffer, S.R. (2008) Macrocyclic spiropiperidine b-secretase inhibitors for the treatment of Alzheimer's disease. WO2008045250A1.
125. Boss, C., Bur, D., Fischli, W., Jenck, F., and Weller, T. (2004) Preparation of piperidines for the treatment of central nervous system disorders. WO2004009549.
126. Boss, C., Bur, D., Fischli, W., Jenck, F., and Weller, T. (2004) Preparation of substituted 3-and 4-(aminomethyl) piperidines for use as b-secretase inhibitors in the treatment of Alzheimer's disease. WO2004002483.
127. Beck, J.P. (2003) Preparation and use of aza-bicyclononanes for the treatment of Alzheimer's disease. WO2003000261.
128. Watanabe, H., Kurasawa, O., Tarui, N., Yorimoto, T., and Hirai, K. (2004) Preparation of indoles as inhibitors against aspartate protease, b-secretase, and amyloid b protein for treatment of nerve disorders and myopathy. JP2004149429.
129. Willems, H., Harris, W., and John, D.E. (2004) A preparation of triazinoindole derivatives as inhibitors of b-secretase (BACE), useful in the treatment of Alzheimer's disease. WO2004063196.
130. Schindelholz, B., Schmid, G., Brigo, A., Milas, D., and Garcia, G. (2006) Preparation of (hetero)aromatic hydrazones as b-secretase inhibitors. WO2006029850.
131. Dietrich, A., Nimz, O., Rester, U., Fecke, W., Haemmerle, M., and Baier, F. (2003) b secretase inhibitors for use in treatment of diseases caused by deposits of b-amyloid peptides. WO2003059346.
132. Huang, D., Luthi, U., Kolb, P., Cecchini, M., Barberis, A., and Caflisch, A. (2006) In silico discovery of b-secretase inhibitors. Journal of the American Chemical Society, 128, 5436-5443.
133. Jeon, S.Y., Bae, K., Seong, Y.H., and Song, K.S. (2003)Green tea catechins as a BACE1 (beta-secretase) inhibitor. Bioorganic & Medicinal Chemistry Letters, 13, 3905-3908.
134. Jeon, S.Y., Kwon, S.H., Seong, Y.H., Bae, K.,Hur, J.M., Lee, Y.Y., Suh, D.Y., and Song, K.S. (2007) Beta-secretase (BACE1)-inhibiting stilbenoids from Smilax rhizoma. Phytomedicine, 14, 403-408.
135. Piazzi, L., Cavalli, A., Colizzi, F., Belluti, F., Bartolini, M., Mancini, F., Recanatini, M., Andrisano, V., and Rampa, A. (2008) Multi-targetdirected coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorganic & Medicinal Chemistry Letters, 18, 423-426.
136. Luthi, U., Huang, D., Kolb, P., Cecchini, M., Majeux, N., Dey, F., Audetat, S.V., Caflisch, A., and Barberis, A. (2006) Aryl urea compounds as b-secretase inhibitors, and use for the treatment of neurodegenerative diseases. WO2006133588.
137. Huang, D., Luthi, U., Kolb, P., Edler, K., Cecchini, M., Audetat, S., Barberis, A., and Caflisch, A. (2005) Discovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations. Journal of Medicinal Chemistry, 48, 5108-5111.
138. Bornemann, K., Trummlitz, G., Beck, B., Sams Dodd, F., Kugler, D., Klinder, K., Dorner Ciossek, C., and Kostka, M. (2005) Method of treating diseases and conditions associated with an altered level of amyloid beta peptides and new enolcarboxamide compounds. US Patent 20050277635A1.
139. Kuglstatter, A., Stahl, M., Peters, J.-U., Huber, W., Stihle, M., Schlatter, D., Benz, J., Ruf, A., Roth, D., Enderle, T., and Hennig, M. (2008) Tyramine fragment binding to BACE-1. Bioorganic & Medicinal Chemistry Letters, 18, 1304-1307.
140. Yang, W., Fucini, R.V., Fahr, B.T., Randal, M., Lind, K.E., Lam, M.B., Lu,W., Lu, Y., Cary, D.R., Romanowski, M.J., Colussi, D., Pietrak, B., Allison, T.J., Munshi, S.K., Penny, D.M., Pham, P., Sun, J., Thomas, A.E., Wilkinson, J.M., Jacobs, J.W., McDowell, R.S., and Ballinger, M.D. (2009) Fragment-based discovery of nonpeptidic BACE-1 inhibitors using tethering. Biochemistry, 48, 4488-4496.
141. Asso, V., Ghilardi, E., Bertini, S., Digiacomo, M.,Granchi, C., Minutolo, F., Rapposelli, S., Bortolato, A., Moro, S., and Macchia, M. (2008) Alpha -naphthylaminopropan-2-ol derivatives as BACE1 inhibitors. ChemMedChem, 3, 1530-1534.
142. Willems, H. (2004) Preparation of piperazines as b-amyloid converting enzyme (BACE) inhibitors for the treatment of Alzheimer's disease. WO2004020422.
143. Willems, H. and Harris, W.H. (2004) Preparation of N-sulfonyl amino acid derivatives for the treatment of Alzheimer's disease. WO2004020402.