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Expert Opinion on Drug Discovery Volume 4, 2009 - Issue 4
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Recent progress in the drug discovery of non-peptidic BACE1 inhibitors

Yoshio Hamada Kyoto Pharmaceutical University, Center for Frontier Research in Medicinal Science, Department of Medicinal Chemistry, Yamashina-ku, Kyoto, Japan
&
Yoshiaki Kiso Kyoto Pharmaceutical University, Center for Frontier Research in Medicinal Science, Department of Medicinal Chemistry, Yamashina-ku, Kyoto, Japan
Pages 391-416 | Published online: 03 Apr 2009

Bibliography

  • Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid β-protein. Ann NY Acad Sci 2000;924:17-25
  • Selkoe DJ. The deposition of amyloid proteins in the aging mammalian brain: implications for Alzheimer's disease. Ann Med 1989;21:73-6
  • Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 1999;399:A23-31
  • Sinha S, Lieberburg I. Cellular mechanisms of β-amyloid production and secretion. Proc Natl Acad Sci USA 1999;96:11049-53
  • Vassar R, Bennett BD, Babu-Khan S, et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735-41
  • Hussain I, Powell D, Howlett DR, et al. Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase. Neuroscience 1999;14(6):419-27
  • Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 1999;402:533-7
  • Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 1999;402:537-40
  • Roberds SL, Anderson J, Basi G, et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum Mol Genetics 2001;10:317-24
  • Turner PR, O'Connor K, Tate WP, Abraham WC. Roles of amyloid precursor protein and its fragment in regulating neural activity, plasticity and memory. Prog Neurobiol 2003;70:1-32
  • Tabaton M, Tamagno E. The molecular link between β- and γ-secretase activity on the amyloid β precursor protein. Cell Mol Life Sci 2007;64:2211-8
  • Ghosh AK, Shin D, Downs D, et al. Design of potent inhibitors for human brain memapsin 2 (β-secretase). J Am Chem Soc 2000;122:3522-3
  • Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science 2000;290:150-3
  • Ghosh AK, Bilcer G, Harwood C, et al. Structure-based design: potent inhibitors of human brain memapsin 2 (β-secretase). J Med Chem 2001;44:2865-8
  • Tang J, Hong L, Ghosh AK. Inhibitors of memapsin 2 and use thereof. PCT Int Appl WO2001000665; 2001
  • Ghosh AK, Devasamudram T, Hong L, et al. Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase). Bioorg Med Chem Lett 2005;15:15-20
  • Shuto D, Kasai S, Kimura T, et al. KMI-008, a Novel β-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: Design and synthesis of substrate-based octapeptides. Bioorg Med Chem Lett 2003;13:4273-6
  • Kimura T, Shuto D, Kasai S, et al. KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine. Bioorg Med Chem Lett 2004;14:1527-31
  • Kimura T, Shuto D, Hamada Y, et al. Design and synthesis of highly active Alzheimer's β-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability. Bioorg Med Chem Lett 2005;15:211-5
  • Asai M, Hattori C, Iwata N, et al. The novel β-secretase inhibitor KMI-429 reduces amyloid β prptide production in amyloid precursor protein transgenic and wild-type mice. J Neurochem 2006;96:533-40
  • Kimura T, Hamada Y, Stochaj M, et al. Design and synthesis of potent β-secretase (BACE1) inhibitors with P1′ carboxylic acid bioisostere. Bioorg Med Chem Lett 2006;16:2380-6
  • Hamada Y, Igawa N, Ikari H, et al. β-Secretase inhibitors: Modification at the P4 position and improvement of inhibitory activity in cultured cells. Bioorg Med Chem Lett 2006;16:4354-9
  • Hamada Y, Abdel-Rahman H, Yamani A, et al. BACE1 inhibitors: Optimization by replacing the P1′ residue with non-acidic moiety. Bioorg Med Chem Lett 2008;18:1649-53
  • Boyd JG, Singleton DH. An inhibitor of β amyloid cleavage enzyme. Eur Pat Appl EP1233021A2; 2002
  • Hu J, Cwi CL, Smiley DL, et al. Design and synthesis of statine-Containing BACE inhibitors. Bioorg Med Chem Lett 2003;13:4335-9
  • Tung JS, Davis DL, Anderson JP, et al. Design of substrate-based inhibitors of human β-secretase. J Med Chem 2002;45:259-62
  • Tamamura H, Kato T, Otaka A, Fujii N. Synthesis of potent β-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure-activity relationship studies. Org Biomol Chem 2003;1:2468-73
  • Miyamoto M, Matsui J, Fukumoto H, Tarui N. Preparation of 2-[2-amino- or 2-(N-heterocyclyl)ethyl]-6-(4-biphenylylmethoxy)tetralin derivatives as β-secretase inhibitors. PCT Int Appl WO2001087293A1; 2001
  • Watanabe H, Kurasawa O, Tarui N, et al. Preparation of indoles as inhibitors against aspartate protease, β-secretase, and amyloid β protein for treatment of nerve disorders and myopathy. Jpn Pat Appl JP2004149429A; 2004
  • Bhisetti GR, Saunders JO, Murcko MA, et al. Preparation of β-carbolines and other inhibitors of BACE-1 aspartic proteinase useful against Alzheimer's and other BACE-mediated diseases. PCT Int Appl WO2002088101A2; 2002
  • Saftig P, Hetman M, Schmahl W, et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 1995;14:3599-608
  • Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 1999;402:533-7
  • Acquati F, Accarino M, Nucci C, et al. The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett 2000;468:59-64
  • Basi G, Frigon N, Barbour R, et al. Antagonistic effects of β-site amyloid precursor protein-cleaving enzymes 1 and 2 on β-amyloid peptide production in cells. J Biol Chem 2003;278:31512-20
  • Sun X, Wang Y, Qing H, et al. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J 2005;19:739-49
  • Fang LY, Hom R, John V, Maillaird M. Preparation of substituted amines for treating Alzheimer's disease. PCT Int Appl WO2002002505A2; 2002
  • Maillaird M, Hom C, Gailunas A, et al. Preparation of substituted amines to treat Alzheimer's disease. PCT Int Appl WO2002002512A2; 2002
  • Beck JP, Gailunas A, Hom R, et al. Preparation of disubstituted amines for treating Alzheimer's disease. PCT Int Appl WO2002002518A2; 2002
  • Beck JP, Gailunas A, Hom R, et al. Preparation of disubstituted amines for treating Alzheimer's disease. PCT Int Appl WO2002002520A2; 2002
  • Schostarez HJ, Chrusciel RA, Centko RS. Acylaminopropylhydrazines as β-secretase inhibitors. PCT Int Appl WO2002094768A2; 2002
  • Schostarez HJ, Chrusciel RA. Preparation of peptide-related hydrazine derivatives for treating Alzheimer's disease. PCT Int Appl WO2002100410A1; 2002
  • Schostarez HJ, Chrusciel RA. Preparation of aminediols as β-secretase inhibitors for the treatment of Alzheimer's and other diseases characterized by deposition of Aβ peptide. PCT Int Appl WO2002100818A2; 2002
  • Maillard M, Tucker JA. Substituted aminoalcohols useful in treatment of Alzheimer's disease. PCT Int Appl WO2002100820A1; 2002
  • John V, Hom R, Tucker J. Preparation of β-hydroxyamine derivatives for the treatment of Alzheimer's disease. PCT Int Appl WO2003002122A1; 2003
  • Schostarez HJ, Chrusciel RA. Preparation of diamine diols as β-secretase inhibitors for the treatment of Alzheimer's disease. PCT Int Appl WO2003006013A1; 2003
  • Schostarez HJ, Chrusciel RA. Preparation of statine derivatives for the treatment of Alzheimer's disease. PCT Int Appl WO2003006021A1; 2003
  • Gailunas A, Hom R, John V, et al. Preparation of N-(3-amino-2-hydroxy-propyl) substituted alkanamides as inhibitors of the β secretase enzyme for treating Alzheimer's disease. PCT Int Appl WO2003006423A1; 2003
  • Schostarez HJ, Chrusciel RA. Preparation of amine diols as β-secretase inhibitors for the treatment of Alzheimer's disease. PCT Int Appl WO2003006453A1; 2003
  • Hom RK, Fang LY, Mamo S, et al. Design and synthesis of statine-based cell-permeable peptidomimetic inhibitors of human β-secretase. J Med Chem 2003;46:1799-802
  • Varghese J, Maillard M, Jagodzinska B, et al. Preparation of N,N'-substituted-1,3-diamino-2-hydroxypropanes for treating Alzheimer's disease. PCT Int Appl WO2003040096A2; 2003
  • Romero AG, Schostarez H, Roels CM. Preparation of amine 1,2- and 1,3-diol alditols and their use for treatment of Alzheimer's disease. PCT Int Appl WO2003043975A1; 2003
  • Brady SF, Singh S, Crouthamel MC, et al. Rational design and synthesis of selective BACE-1 inhibitors. Bioorg Med Chem Lett 2004;14:601-4
  • Coburn CA, Stachel SJ, Li YM. Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases. J Med Chem 2004;47:6117-9
  • Stachel SJ, Coburn CA, Steele TG, et al. Structure-based design of potent and selective cell-permeable inhibitors of human β-secretase (BACE-1). J Med Chem 2004;47:6447-50
  • Stachel SJ, Coburn CA, Steele TG, et al. Conformationally biased P3 amide replacements of β-secretase inhibitors. Bioorg Med Chem Lett 2006;16:641-4
  • Coburn CA, Stachel SJ, Jones KG, et al. BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres. Bioorg Med Chem Lett 2006;16:3635-8
  • Rajapakse HA, Nantermet PG, Selnick HG, et al. Discovery of oxadiazoyl tertiary carbinamine inhibitors of β-secretase (BACE-1). J Med Chem 2006;49:7270-3
  • McGaughey GB, Colussi D, Graham SL, et al. β-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites. Bioorg Med Chem Lett 2007;17:1117-21
  • Stauffer SR, Stanton MG, Gregro AR, et al. Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation. Bioorg Med Chem Lett 2007;17:1788-92
  • Lindsley SR, Moore KP, Rajapakse HA, et al. Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg Med Chem Lett 2007;17:4057-61
  • Moore KP, Zhu H, Rajapakse HA, et al. Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg Med Chem Lett 2007;17:5831-5
  • Barrow JC, Stauffer SR, Rittle KE, et al. Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of β-secretase. J Med Chem 2008;51:6259-62
  • Uchikawa O, Aso K, Koike T, et al. Preparation of benzamide derivatives as β-secretase inhibitors. PCT Int Appl WO2004014843A1; 2004
  • Decicco CP, Tebben AJ, Thompson LA, Combs AP. Preparation of novel α-amino-γ-lactams as β-secretase inhibitors. PCT Int Appl WO2004013098A1; 2004
  • Freskos JN, Fobian YM, Benson TE, et al. Design of potent inhibitors of human β-secretase. Part 1. Bioorg Med Chem Lett 2007;17:73-7
  • Kortum SW, Benson TE, Bienkowski MJ, et al. Potent and selective isophthalamide S2 hydroxyethylamine inhibitors of BACE1. Bioorg Med Chem Lett 2007;17:3378-83
  • Demont EH, Faller A, MacPherson DT, et al. Preparation of hydroxyethylamine derivatives for the treatment of Alzheimer's disease. PCT Int Appl WO2004050619A1; 2004
  • Demont EH, Redshaw S, Walter DS. Preparation of hydroxyethylamine derivatives for the treatment of Alzheimer's disease. PCT Int Appl WO2004080376A2; 2004
  • Demont EH, Redshaw S, Walter DS. Preparation of hydroxydiaminopropyl tricyclic indolecarboxamides for treatment of β-amyloid related disease. PCT Int Appl WO2004094430A1; 2004
  • Demont EH, Redshaw S, Walter DS. Preparation of 3-(1,1-dioxotetrahydro-1, 2-thiazin-2-yl) or 3-(1,1-dioxo-isothiazolidin-2-yl) substituted benzamide compounds for treatment of Alzheimer's disease. PCT Int Appl WO2004111022A1; 2004
  • Redshaw S, Demont EH, Walter DS. Preparation of tricyclic indole hydroxyethylamine derivatives and their use in the treatment of Alzheimer's disease. PCT Int Appl WO2005058915A1; 2005
  • Demont EH, Redshaw S, Walter DS. Preparation of N,N'-substituted-1,3-diamino-2-oxopropane derivatives as Asp2 inhibitors for use against diseases characterized by elevated β-amyloid levels or β-amyloid deposits, particularly Alzheimer's disease. PCT Int Appl WO2005113525A1; 2005
  • Demont EH, Redshaw S, Walter DS. Heterocyclic ketone compounds for treating Alzheimer's disease. PCT Int Appl WO2006040149A1; 2006
  • Demont EH, Redshaw S, Walter DS. Preparation of substituted hydroxyethylamine compounds for treating Alzheimer's disease. PCT Int Appl WO2006040151A1; 2006
  • Demont EH, Redshaw S, Walter DS. Tricyclic indole derivatives for use in the treatment of Alzheimer's disease. PCT Int Appl WO2006040148A1; 2006
  • Clarke B, Demont E, Dingwall C, et al. BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs). Bioorg Med Chem Lett 2008;18:1011-6
  • Clarke B, Demont E, Dingwall C, et al. BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character. Bioorg Med Chem Lett 2008;18:1017-21
  • Beswick P, Charrier N, Clarke B, et al. BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg Med Chem Lett 2008;18:1022-6
  • Hussain I, Hawkins J, Harrison D, et al. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases β-cleavage of amyloid precursor protein and amyloid-β production in vivo. J Neurochem 2007;100(3):802-9
  • Ghosh AK, Kumaragurubaran N, Hong L, et al. Potent memapsin 2 (β-secretase) inhibitors: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorg Med Chem Lett 2008;18:1031-6
  • Iserloh U, Wu Y, Cumming JN, et al. Potent pyrrolidine- and piperidine-based BACE1 inhibitors. Bioorg Med Chem Lett 2008;18:414-7
  • Iserloh U, Pan J, Stamfold AW, et al. Discovery of an orally efficacious 4-phenoxypyrrolidine-based BACE-1 inhibitor. Bioorg Med Chem Lett 2008;18:418-22
  • Hamada Y, Ohta H, Miyamoto N, et al. Novel non-peptidic and small-sized BACE1 inhibitors. Bioorg Med Chem Lett 2008;18:1654-8
  • Cole DC, Manas ES, Stock JR, et al. Acylguanidines as small-molecule β-secretase inhibitors. J Med Chem 2006;49:6158-61
  • Fobare WF, Solvibile WR, Robichaud AJ, et al. Thiophene substituted acylguanidines as BACE1 inhibitors. Bioorg Med Chem Lett 2007;17:5353-6
  • Jennings LD, Cole DC, Stock JR, et al. Acylguanidine inhibitors of β-secretase: optimization of the pyrrole ring substituents extending into the S′1 substrate binding pocket. Bioorg Med Chem Lett 2008;18:767-71
  • Cole DC, Stock JR, Chopra R, et al. Acylguanidine inhibitors of β-secretase: Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets. Bioorg Med Chem Lett 2008;18:1063-6
  • Hu B. Preparation of terphenylguanidines as β-secretase inhibitors for inhibition of the formation of β-amyloid deposits and neurofibrillary tangles present in neurodegenerative diseases. US Pat Appl US2006183943A1; 2006
  • Cole DC, Manas ES, Jennings LD, et al. Preparation of azolylacylguanidines as β-secretase inhibitors. US Pat Appl US2006183790A1; 2006
  • Fobare WF, Solvibile WR. Preparation of thienyl and furyl acylguanidines as β-secretase (BACE) inhibitors. US Pat Appl US2006183792A1; 2006
  • Malamas MS, Erdei JJ, Gunawan IS, et al. Preparation of amino-5,5-diphenylimidazolone derivatives for inhibition of beta-secretase and treatment of β-amyloid-related diseases. US Pat Appl US2005282825A1; 2005
  • Malamas MS, Erdei JJ, Gunawan IS, et al. Preparation of diphenylimidazopyrimidine and -imidazole amines as selective inhibitors of β-secretase for use against Alzheimer's disease and other disorders. US Pat Appl US2005282826A1; 2005
  • Malamas MS, Erdei JJ, Gunawan IS, et al. Preparation of 8,8-diphenyl-2,3,4, 8-tetrahydroimidazo[1,5-a]pyrimidin-6-amines as β-secretase inhibitors for the treatment of Alzheimer's disease and related disorders. PCT Int Appl WO2006076284A2; 2006
  • Malamas MS, Fobare WF, Solvibile WR, et al. Amino-pyridines as inhibitors of β-secretase and their preparation, and pharmaceutical compositions. US Pat Appl US2006173049A1; 2006
  • Zhou PM, Michael S, Li Y, et al. Preparation of aminoheteroarylimidazolone compounds for use as β-secretase modulators to treat β-amyloid and neurofibrillary tangle associated diseases. US Pat Appl US2007004730A1; 2007
  • Malamas MS, Zhou P, Fobare WF, et al. Preparation of amino-5-(5-membered)hetero-arylimidazolone compounds as β-secretase modulators for treating diseases involving β-amyloid deposits and neurofibrillary tangles. US Pat Appl US2007004786A1; 2007
  • Malamas MS, Gunawan IS, Erdei JJ, et al. Cycloalkyl amino-hydantoin compounds and use thereof for β-secretase modulation and treatment of diseases with β-amyloid deposits and neurofibrillary tangles. US Pat Appl US2007027199A1; 2007
  • Malamas MS, Erdei JJ, Fobare WF, et al. Preparation of imidazolone derivatives as inhibitors of β-secretase. US Pat Appl US2007072925A1; 2007
  • Zhou P, Bernotas RC, Li Y, et al. Preparation of 2-amino-5-phenyl-5-piperidinylimidazolone compounds and use thereof for β-secretase modulation. PCT Int Appl WO2007078813A2; 2007
  • Quagliato DA, Andrae PM, Fan Y. Preparation of spirodibenzoannulene-imidazolones as inhibitors of β-secretase (BACE). US Pat Appl US2007203116A1; 2007
  • Malamas MS, Barnes KD, Johnson MR. Imidazole amines as inhibitors of β-secretase and their preparation, pharmaceutical compositions and use in the treatment of diseases associated with elevated β-amyloid deposits and β-amyloid levels. PCT Int Appl WO2008022024A2; 2008
  • Malamas MS, Robichaud AJ, Porte AM, et al. Amino-5-[substituted-4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds as β-secretase inhibitors and their preparation, and use in the treatment of β-amyloid deposits and neurofibrillary tangles. PCT Int Appl WO2008115552A1; 2008
  • Malamas MS, Robichaud AJ, Porte AM, et al. Preparation of amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone derivatives as inhibitors of β-secretase. PCT Int Appl WO2008118379A2; 2008
  • Baxter EW, Conway KA, Kennis L, et al. 2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (β-site APP cleaving enzyme): use of structure based design to convert a micromolar hit into a nanomolar lead. J Med Chem 2007;50:4261-4
  • Geschwindner S, Olsson LL, Albert JS, et al. Discovery of a novel warhead against β-secretase through fragment-based lead generation. J Med Chem 2007;50:5903-11
  • Edwards PD, Albert JS, Sylvester M, et al. Application of fragment-based lead generation to the discovery of novel, cyclic amidine β-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency. J Med Chem 2007;50:5912-25
  • Congreve M, Aharony D, Albert J, et al. Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of β-secretase. J Med Chem 2007;50:1124-32
  • Huang D, Luethi U, Kolb P, et al. Discovery of cell-permeable non-peptide inhibitors of β-secretase by high-throughput docking and continuum electrostatics calculations. J Med Chem 2005;48:5108-11
  • Huang D, Luethi U, Kolb P, et al. In silico discovery of β-secretase inhibitors. J Am Chem Soc 2006;128(16):5436-43
  • Kolb P, Caflisch A. Automatic and efficient decomposition of two-dimensional structures of small molecules for fragment-based high-throughput docking. J Med Chem 2006;49:7384-92
  • Kuglstatter A, Stahl M, Peters JU, et al. Tyramine fragment binding to BACE-1. Bioorg Med Chem Lett 2008;18:1304-7

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