Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Dual binding site acetylcholinesterase inhibitors have recently emerged as a new class of anti-Alzheimer agents with potential to positively modify the course of the disease. These compounds exhibit a multifunctional pharmacological profile arising from interaction with several biological targets involved upstream and downstream in the neurodegenerative cascade of Alzheimer's disease (AD). The primary target of these compounds is the enzyme acetylcholinesterase (AChE). Interaction of dual binding site AChE inhibitors with AChE results in a potent inhibitory activity of AChE and AChE-induced β-amyloid peptide (Aβ) aggregation. Some dual binding site AChE inhibitors take on added value a significant ability to additionally inhibit the enzymes butyrylcholinesterase and BACE-1, involved in the co-regulation of the hydrolysis of the neurotransmitter acetylcholine and in Aβ formation, respectively. The structural determinants which mediate the interaction of dual binding site AChE inhibitors with these three important enzymes for AD treatment are herein re-viewed. © 2010 Bentham Science Publishers Ltd.

Registro:

Documento: Artículo
Título:Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-alzheimer agents
Autor:Galdeano, C.; Viayna, E.; Arroyo, P.; Bidon-Chanal, A.; Blas, J.R.; Muñoz-Torrero, D.; Luque, F.J.
Filiación:Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, E-08028, Barcelona, Spain
Laboratorio de Modelado Molecular, Química Inorgánica, Analítica y Química Física, INQUIMAE (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria - Pabellón II 1piso, C1428EHA, Buenos Aires, Argentina
Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, E-08028, Barcelona, Spain
Palabras clave:Acetylcholinesterase; Bace-1; Butyrylcholinesterase; Drug-target interactions; Structure-based drug design; 8 ( 2,6 dimethylmorpholino)octylcarbamoyleseroline; acetylcholine; acetylcholinesterase; aminopyridine derivative; amyloid beta protein; ap 2238; beta secretase; beta secretase inhibitor; butyrylcholinesterase 1; cholinesterase; cholinesterase inhibitor; decamethonium; donepezil; galantamine; gallamine; huperzine A; huprine X; mf 268; neuromuscular depolarizing agent; nf 595; nootropic agent; peptidomimetic agent; physostigmine; physostigmine derivative; propidium iodide; pyrimidine derivative; sulfonamide; tacrine; thioflavine; triazole derivative; unclassified drug; unindexed drug; xanthostigmine; Alzheimer disease; article; catalysis; complex formation; crystal structure; degenerative disease; disease course; drug binding site; drug inhibition; drug potency; enzyme activity; human; hydrolysis; IC 50; neurotransmission; nonhuman; oligomerization; priority journal; X ray crystallography
Año:2010
Volumen:16
Número:25
Página de inicio:2818
Página de fin:2836
DOI: http://dx.doi.org/10.2174/138161210793176536
Título revista:Current Pharmaceutical Design
Título revista abreviado:Curr. Pharm. Des.
ISSN:13816128
CODEN:CPDEF
CAS:acetylcholine, 51-84-3, 60-31-1, 66-23-9; acetylcholinesterase, 9000-81-1; amyloid beta protein, 109770-29-8; cholinesterase, 9001-08-5; decamethonium, 1420-40-2, 156-74-1, 3198-38-7, 541-22-0; donepezil, 120011-70-3, 120014-06-4, 142057-77-0; galantamine, 1953-04-4, 357-70-0; gallamine, 153-76-4; huperzine A, 102518-79-6, 92138-20-0; physostigmine, 57-47-6, 64-47-1; propidium iodide, 25535-16-4; tacrine, 1684-40-8, 3198-41-2, 321-64-2; thioflavine, 2390-54-7
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13816128_v16_n25_p2818_Galdeano

Referencias:

  • (2009) Alzheimer's Disease Facts and Figures.Alzheimers Dementia, 5, pp. 234-270. , Alzheimer's Association
  • Wimo, A., Winblad, B., Jönsson, L., The worldwide societal costs ofdementia: Estimates for 2009 (2010) Alzheimers Dementia, 6, pp. 98-103
  • Yamin, G., Ono, K., Inayathullah, M., Teplow, D.B., Amyloid β-protein assembly as a therapeutic target of Alzheimer's disease (2008) CurrPharm Des, 14, pp. 3231-3246
  • Ghosh, A.K., Gemma, S., Tang, J., β-Secretase as a therapeutic targetfor Alzheimer's disease (2008) Neurotherapeutics, 5, pp. 399-408
  • Silvestri, R., Boom in the development of non-peptidic -secretase(BACE-1) inhibitors for the treatment of Alzheimer's disease (2009) Med Res Rev, 29, pp. 295-338
  • Sussman, J.L., Harel, M., Frolow, F., Atomic structure of acetyl-cholinesterase from Torpedo californica, a prototypic acetylcho-line-binding protein (1991) Science, 253, pp. 872-879
  • Lane, R.M., Potkin, S.G., Enz, A., Targeting acetylcholinesterase and butyrylcholinesterase in dementia (2006) Int J Neuropsychopharmacol, 9, pp. 101-124
  • Lane, R.M., He, Y., Emerging hypotheses regarding the influence ofbutyrylcholinesterase-K variant, APOE e4, and hyperhomocys-teinemia in neurodegenerative dementias (2009) Med Hypothes, 73, pp. 230-250
  • Greig, N.H., Utsuki, T., Ingram, D.K., Selective butyrylcho-linesterase inhibition elevates brain acetylcholine, augments learn-ing and lowers Alzheimer β-amyloid peptide in rodent (2005) Proc NatlAcad Sci USA, 102, pp. 17213-17218
  • Weinstock, M., Selectivity of cholinesterase inhibition: Clinicalimplications for the treatment of Alzheimer's disease (1999) CNS Drugs, 12, pp. 307-323
  • Giacobini, E., Cholinesterase inhibitors: New roles and the rapeuticalternatives (2004) Pharmacol Res, 50, pp. 433-440
  • Venneri, A., McGeown, W.J., Shanks, M.F., Empirical evidence ofneuroprotection by dual cholinesterase inhibition in Alzheimer'sdisease (2005) Neuropharmacol Neurotoxicol, 16, pp. 107-110
  • Giacobini, E., Spiegel, R., Enz, A., Veroff, A.E., Cutler, N.R., Inhibition ofacetyl- and butyryl-cholinesterase in the cerebrospinal fluid of pa-tients with Alzheimer's disease by rivastigmine: Correlation withcognitive benefit (2002) J Neural Transm, 109, pp. 1053-1065
  • Inestrosa, N.C., Alvarez, A., Pérez, C.A., Acetylcholinesteraseaccelerates assembly of amyloid-β-peptides into Alzheimer's fi-brils: Possible role of the peripheral site of the enzyme (1996) Neuron, 16, pp. 881-891
  • Inestrosa, N.C., Dinamarca, M.C., Alvarez, A., Amyloid cholinesteraseinteractions. Implications for Alzheimer's disease (2008) FEBS J, 275, pp. 625-632
  • Rees, T., Hammond, P.I., Soreq, H., Younkin, S., Brimijoin, S., Acetyl-cholinesterase promotes beta-amyloid plaques in cerebral cortex (2003) Neurobiol Aging, 24, pp. 777-787
  • Alvarez, A., Alarcón, R., Opazo, C., Stable complexes involvingacetylcholinesterase and amyloid- peptide change the biochemicalproperties of the enzyme and increase the neurotoxicity of Alz-heimer's fibrils (1998) J Neurosci, 18, pp. 3213-3223
  • Reyes, A.E., Chacón, M.A., Dinamarca, M.C., Cerpa, W., Morgan, C., Inestrosa, N.C., Acetylcholinesterase-A complexes are more toxicthan A fibrils in rat hippocampus: Effect on rat -amyloid aggre-gation, laminin expression, reactive astrocytosis, and neuronal cellloss (2004) Am J Pathol, 164, pp. 163-174
  • Rees, T.M., Berson, A., Sklan, E.H., Memory deficits correlatingwith acetylcholinesterase splice shift and amyloid burden in doublytransgenic mice (2005) Curr Alzheimer Res, 2, pp. 291-300
  • Hamley, I.W., Peptide fibrillization (2007) Angew Chem Int Ed, 46, pp. 8128-8147
  • Espallergues, J., Galvan, L., Sabatier, F., Rana-Poussine, V., Maurice, T., Chatonnet, A., Behavioral phenotyping of heterozygous acetylcho-linesterase knockout (AChE+/) mice showed no memory enhance-ment but hyposensitivity to amnesic drugs (2010) Behav Brain Res, 206, pp. 263-273
  • de Ferrari, G.V., Canales, M.A., Shin, I., Weiner, L.M., Silman, I., Ine-Strosa, N.C., A structural motif of acetylcholinesterase that promotesamyloid beta-peptide fibril formation (2001) Biochemistry, 40, pp. 10447-10457
  • Diamant, S., Podoly, E., Friedler, A., Ligumsky, H., Livnah, O., Soreq, H., Butyrylcholinesterase attenuates amyloid fibril formation in vitro (2006) Proc Natl Acad Sci USA, 103, pp. 8628-8633
  • Cavalli, A., Bolognesi, M.L., Capsoni, S., A small moleculetargeting the multifactorial nature of Alzheimer's disease (2007) Angew Chem Int Ed, 46, pp. 3689-3692
  • Pang, Y.P., Quiram, P., Jelacic, T., Hong, F., Brimijoin, S., Highly potent,selective, low cost bis-tetrahydroaminacrine inhibitors of acetyl-cholinesterase (1996) J Biol Chem, 271, pp. 23646-22349
  • Li, W., Mak, M., Jiang, H., Novel anti-Alzheimer's dimer bis(7)-cognitin: Cellular and molecular mechanisms of neuroprotectionthrough multiple targets (2009) Neurotherapeutics, 6, pp. 187-201
  • http://www.noscira.com; Castro, A., Martinez, A., Peripheral and dual binding site acetylcho-linesterase inhibitors: Implications in treatment of Alzheimer's dis-ease (2001) Mini Rev Med Chem, 1, pp. 267-272
  • Cavalli, A., Bolognesi, M.L., Minarini, A., Multi-target-directedligands to combat neurodegenerative diseases (2008) J Med Chem, 51, pp. 347-372
  • Muñoz-Torrero, D., Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer's disease (2008) Curr Med Chem, 15, pp. 2433-2455
  • García-Palomero, E., Muñoz, P., Usan, P., Potent -amyloidmodulators (2008) Neurodegener Dis, 5, pp. 153-156
  • Loudwig, S., Nicolet, Y., Masson, P., Photoreversible inhibitionof cholinesterases: Catalytic serine-labeled caged butyrylcholineste-rase (2003) ChemBioChem, 4, pp. 762-767
  • Savini, L., Gaeta, A., Fattorusso, C., Specific targeting of acetyl-cholinesterase and butyrylcholinesterase recognition sites. Rationaldesign of novel, selective, and highly potent cholinesterase inhibi-tors (2003) J Med Chem, 46, pp. 1-4
  • Campiani, G., Fattorusso, C., Butini, S., Development of molecular probes for the identification of extra interaction sites in the mid-gorge and peripheral sites of butyrylcholinesterase (BuChE). Rational design of novel, selective, and highly potent BuChE inhibitors (2005) J Med Chem, 48, pp. 1919-1929
  • Masson, P., Froment, M.T., Fort, S., Butyrylcholinesterase-catalyzed hydrolysis of N-methylindoxyl acetate: Analysis of volume changes upon reaction and hysteretic behavior (2002) Biochim Bio-phys Acta, 1597, pp. 229-243
  • Lin, G., Chen, G.H., Lu, C.P., Yeh, S.C., QSARs for peripheral anionicsite of butyrylcholinesterase with inhibitions by 4-acyloxy-biphenyl-4'-N-butylcarbamates (2005) QSAR Comb Sci, 24, pp. 943-952
  • Camps, P., Formosa, X., Muñoz-Torrero, D., Petrignet, J., Badia, A., ClosMV. Synthesis and pharmacological evaluation of huprine tacrineheterodimers: Subnanomolar dual binding site acetylcholinesteraseinhibitors (2005) J Med Chem, 48, pp. 1701-1714
  • Camps, P., Formosa, X., Galdeano, C., Novel Donepezil basedinhibitors of acetyl- and butyryl cholinesterase and acetylcho-linesterase-induced -amyloid aggregation (2008) J Med Chem, 51, pp. 3588-3598
  • Fang, L., Kraus, B., Lehmann, J., Heilmann, J., Zhang, Y., Decker, M., Design and synthesis of tacrine-ferulic acid hybrids as multi-potentanti-Alzheimer drug candidates (2008) Bioorg Med Chem Lett, 18, pp. 2905-2909
  • Fernández-Bachiller, M.I., Pérez, C., Campillo, N.E., Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's dis-ease, with cholinergic, antioxidant, and neuroprotective properties (2009) Chem Med Chem, 4, pp. 828-841
  • Fang, L., Appenroth, D., Decker, M., Synthesis and biologicalevaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates (2008) J Med Chem, 51, pp. 713-716
  • Elsinghorst, P.W., Cieslik, J.S., Mohr, K., Tränkle, C., Gütschow, M., Firstgallamine-tacrine hybrid: Design, and characterization at cho-linesterases and the M2 muscarinic receptor (2007) J Med Chem, 50, pp. 5685-5695
  • Muñoz-Ruiz, P., Rubio, L., García-Palomero, E., Design, synthe-sis, and biological evaluation of dual binding site acetylcho-linesterase inhibitors: New disease-modifying agents for Alz-heimer's disease (2005) J Med Chem, 48, pp. 7223-7233
  • Bolognesi, M.L., Cavalli, A., Valgimigli, L., Multi-target-directeddrug design strategy: From a dual binding site acetylcholinesteraseinhibitor to a trifunctional compound against Alzheimer's disease (2007) J Med Chem, 50, pp. 6446-6449
  • Harrison, S.M., Harper, A.J., Hawkins, J., BACE1 (β-secretase)transgenic and knockout mice: Identification of neurochemicaldeficits and behavioral changes (2003) Mol Cell Neurosci, 24, pp. 646-655
  • McConlogue, L., Buttini, M., Anderson, J.P., Partial reduction ofBACE1 has dramatic effects on Alzheimer plaque and synaptic pa-thology in APP transgenic mice (2007) J Biol Chem, 282, pp. 26326-26334
  • Hong, L., Koelsch, G., Lin, X., Structure of the protease domainof memapsin 2 (β-secretase) complexed with inhibitor (2000) Science G, 290, pp. 150-153
  • Hong, L., Turner, R.T., Koelsch, G., Shin, D., Ghosh, A.K., Tang, J., Crystal structure of memapsin 2 (β-secretase) in complex with aninhibitor OM00-3 (2002) Biochemistry, 41, pp. 10963-10967
  • Mancini, F., Naldi, M., Cavrini, V., Andrisano, V., Multiwell fluoromet-ric and colorimetric microassays for the evaluation of beta-secretase (BACE-1) inhibitors (2007) Anal Bioanal Chem, 388, pp. 1175-1183
  • Fu, H., Li, W., Luo, J., Promising anti-Alzheimer's dimer bis(7)-tacrine reduces β-amyloid generation by directly inhibiting BACE-1 activity (2008) Biochem Biophys Res Commun, 366, pp. 631-636
  • Rosini, M., Andrisano, V., Bartolini, M., Melchiorre, C., Organic Com-pounds Useful For the Treatment of Alzheimer's Disease, their Useand Method of Preparation, , WO 2006/080043 A2
  • Piazzi, L., Cavalli, A., Colizzi, F., Multi-target-directed coumarinderivatives: HAChE and BACE1 inhibitors as potential anti-Alzheimer compounds (2008) Bioorg Med Chem, 18, pp. 423-426
  • Camps, P., Formosa, X., Galdeano, C., Pyrano [3,2-c]quinoline 6-chlorotacrine hybrids as a novel family of acetylcho-linesterase- and -amyloid-directed anti-Alzheimer compounds (2009) J Med Chem, 52, pp. 5365-5379
  • Raves, M.L., Harel, M., Pang, Y.P., Silman, I., Kozikowski, A.P., Sussman, J.L., Structure of acetylcholinesterase complexed with the nootropicalkaloid, (-)-huperzine A (1997) Nature Struct Biol, 4, pp. 57-63
  • Dvir, H., Jiang, H.L., Wong, D.M., X-ray structures of Torpedocalifornica acetylcholinesterase complexed with (+)-huperzine Aand (-)-huperzine-B: Structural evidence for an active site rear-rangement (2002) Biochemistry, 41, pp. 10810-10818
  • Barril, X., Kalko, S.G., Orozco, M., Luque, F.J., Rational design ofreversible acetylcholinesterase inhibitors (2002) Mini Rev Med Chem, 2, pp. 27-36
  • Harel, M., Schalk, I., Ehret-Sabatier, L., Quaternary ligandbinding to aromatic residues in the active-site gorge of acetylcho-linesterase (1993) Proc Nat Acad Sci USA, 90, pp. 9031-9035
  • Camps, P., Muñoz-Torrero, D., Tacrine-Huperzine, A., Hybrids (hupri-nes): A new class of highly potent and selective acetylcho-linesterase inhibitors of interest for the treatment of Alzheimer dis-ease (2001) Mini Rev Med Chem, 1, pp. 163-174
  • Camps, P., El Achab, R., Görbig, D.M., Synthesis, in vitro phar-macology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potentialinterest for the treatment of Alzheimer's disease (1999) J Med Chem, 42, pp. 3227-3242
  • Barril, X., Orozco, M., Luque, F.J., Predicting relative binding freeenergies of tacrine-huperzine A hybrids as inhibitors of acetylcho-linesterase (1999) J Med Chem, 42, pp. 5110-5119
  • Camps, P., El Achab, R., Morral, J., New tacrine-huperzine Ahybrids (huprines): Highly potent tight-binding acetylcho-linesterase inhibitors of interest for the treatment of Alzheimer'sdisease (2000) J Med Chem, 43, pp. 4657-4666
  • Dvir, H., Wong, D.M., Harel, M., 3D structure of Torpedo cali-fornica acetylcholinesterase complexed with huprine X at 2.1 Åresolution: Kinetic and molecular dynamic correlates (2002) Biochemistry, 41, pp. 2970-2981
  • Camps, P., Gómez, E., Muñoz-Torrero, D., Binding of 13-amidopurines to acetylcholinesterase: Exploring the ligand-inducedconformational change of the Gly117-Gly118 peptide bond in theoxyanion hole (2006) J Med Chem, 49, pp. 6833-6840
  • Pilger, C., Bartolucci, C., Lamba, D., Tropsha, A., Fels, G., Accurateprediction of the bound conformation of galanthamine in the activesite of Torpedo californica acetylcholinesterase using moleculardocking (2001) J Mol Graphics Model, 19, pp. 288-296
  • Bartolucci, C., Pilger, C., Fels, G., Lamba, D., Three-dimensionalstructure of a complex of galanthamine (Nivalin) with acetylcho-linesterase from Torpedo californica: Implications for the design ofnew anti-Alzheimer drugs (2001) Proteins: Struct Funct Bioinf, 42, pp. 182-191
  • Greenblatt, H.M., Kryger, G., Lewis, T., Silman, I., Sussman, J.L., Struc-ture of acetylcholinesterase complexed with (-)-galanthamine at2.3 Å resolution (1999) FEBS Lett, 463, pp. 321-326
  • Bourne, Y., Taylor, P., Radi, Z., Marchot, P., Structural insights intoligand interactions at the acetylcholinesterase peripheral anionicsite (2003) EMBO J, 22, pp. 1-12
  • Cavalli, A., Bottegoni, G., Raco, C., de Vivo, M., Recanatini, M.A., Computational study of the binding of propidium to the peripheralanionic site of human acetylcholinesterase (2004) J Med Chem, 47, pp. 3991-3999
  • Szegletes, T., Mallender, W.D., Rosenberry, T.L., Nonequilibriumanalysis alters the mechanistic interpretation of inhibition of acetyl-cholinesterase by peripheral site ligands (1998) Biochemistry, 37, pp. 4206-4216
  • Harel, M., Sonoda, L.K., Silman, I., Sussman, J.L., Rosenberry, T.L., Crystal structure of thioflavin T bound to the peripheral site ofTorpedo californica acetylcholinesterase reveals how thioflavin Tacts as a sensitive fluorescent reporter of ligand binding to the acy-lation site (2008) J Am Chem Soc, 130, pp. 7856-7861
  • Kryger, G., Silman, I., Sussman, J.L., Structure of acetylcholinesterasecomplexed with E2020 (Aricept): Implications for the design ofnew anti-Alzheimer drugs (1999) Structure, 7, pp. 297-307
  • Rydberg, E.H., Brumshtein, B., Greenblatt, H.M., Complexes ofalkylene-linked tacrine dimers with Torpedo californica acetylcho-linesterase: Binding of bis(5)-tacrine produces a dramatic rear-rangement in the active-site gorge (2006) J Med Chem, 49, pp. 5491-5500
  • Colletier, J.P., Sanson, B., Bachon, F., Conformational flexibilityin the peripheral site of Torpedo californica acetylcholinesteraserevealed by the complex structure with a bifunctional inhibitor (2006) J Am Chem Soc, 128, pp. 4526-4527
  • Gemma, S., Gabellieri, E., Huleatt, P., Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites (2006) J Med Chem, 49, pp. 3421-3425
  • Haviv, H., Wong, D.M., Greenblatt, H.M., Crystal packing mediates enantioselective ligand recognition at the peripheral site ofacetylcholinesterase (2005) J Am Chem Soc, 127, pp. 11029-11036
  • Bourne, Y., Kolb, H.C., Radic, Z., Sharpless, K.B., Taylor, P., Marchot, P., Freeze-frame inhibitor captures acetylcholinesterase in a uniqueconformation (2004) Proc Natl Acad Sci USA, 101, pp. 1449-1454
  • Senapati, S., Bui, J.M., McCammon, J.A., Induced fit in mouse acetyl-cholinesterase upon binding a femtomolar inhibitor: A moleculardynamics study (2005) J Med Chem, 48, pp. 8155-8162
  • Wong, D.M., Greenblatt, H.M., Dvir, H., Acetylcholinesterasecomplexed with bivalent ligands related to huperzine A: Experi-mental evidence for species-dependent protein-ligand complemen-tarity (2003) J Am Chem Soc, 125, pp. 363-373
  • Greenblatt, H.M., Guillou, C., Guénard, D., The complex of abivalent derivative of galanthamine with Torpedo acethylcho-linesterase displays drastic deformation of the active-site gorge:Implications for structure-based drug design (2004) J Am Chem Soc, 126, pp. 15405-15411
  • Bartolucci, C., Haller, L.A., Jordis, U., Fels, G., Lamba, D., ProbingTorpedo californica acetylcholinesterase catalytic gorge with twonovel bis-functional galanthamine derivatives (2010) J Med Chem, 53, pp. 745-751
  • Adcock, S.A., McCammon, J.A., Molecular dynamics: Survey ofmethods for simulating the activity of proteins (2006) Chem Rev, 106 (1589), p. 615
  • Kua, J., Zhang, Y., McCammon, J.A., Studying enzyme binding speci-ficity in acetylcholinesterase using a combined molecular dynamicsand multiple docking approach (2002) J Am Chem Soc, 124, pp. 8260-8267
  • Bartolucci, C., Perola, E., Cellai, L., Brufani, M., Lamba, D., Backdoor opening implied by the crystal structure of a carbamoylatedacetylcholinesterase (1999) Biochemistry, 38, pp. 5714-5719
  • Rampa, A., Bisi, A., Valenti, P., Acetylcholinesterase inhibitors:Synthesis and structure-activity relationships of [N-methyl-N-(3-alkylcarbamoyloxyphenyl)-methyl]aminoalkoxyheteroaryl derivatives (1998) J Med Chem, 41, pp. 3976-3986
  • Rampa, A., Piazzi, L., Belluti, F., Acetylcholinesterase inhibitors:SAR and kinetic studies on [N-methyl-N-(3-alkylcarbamoyloxyphenyl)-methyl]aminoalkoxyaryl derivatives (2001) J Med Chem, 44, pp. 3810-3820
  • Belluti, F., Rampa, A., Piazzi, L., Cholinesterase inhibitors:Xanthostigmine derivatives blocking the acetylcholinesterase-induced -amyloid aggregation (2005) J Med Chem, 48, pp. 4444-4456
  • Nachon, F., Nicolet, Y., Viguié, N., Engineering of a monomericand low-glycosylated form of human butyrylcholinesterase (2002) Eur J Biochem, 269, pp. 630-637
  • Nicolet, Y., Lockridge, O., Masson, P., Fontecilla-Camps, J.C., Nachon, F., Crystal structure of human butyrylcholinesterase and of its com-plexes with substrate and products (2003) J Biol Chem, 278, pp. 41141-41147
  • Ngamelue, M.N., Homma, K., Lockridge, O., Asojo, O.A., Crystallization and X-ray structure of full-length recombinant human butyryl-cholinesterase (2007) Acta Cryst, F63, pp. 723-727
  • Radic, Z., Pickering, N.A., Vellom, D.C., Camp, S., Taylor, P., Threedistinct domains in the cholinesterase molecule confer selectivityfor acetyl- and butyrylcholinesterase inhibitors (1993) Biochemistry, 32, pp. 12074-12084
  • Butini, S., Campiani, G., Borriello, M., Exploiting protein fluc-tuations at the active-site gorge of human cholinesterases: Futureoptimization of the design strategy to develop extremely potent in-hibitors (2008) J Med Chem, 51, pp. 3154-3170
  • Elsinghorst, P.W., Cieslik, J.S., Mohr, K., Tränkle, C., Gütschow, M., Firstgallamine-tacrine hybrid: Design and characterization at cho-linesterases and the M2 muscarinic receptor (2007) J Med Chem, 50, pp. 5685-5695
  • Tumiatti, V., Milelli, A., Minarini, A., Structure-activity relation-ships of acetylcholinesterase noncovalent inhibitors based on apolyamine backbone. 4. Further investigation on the inner spacer (2008) J Med Chem, 51, pp. 7308-7312
  • Pan, L., Tan, J.H., Hou, J.Q., Huang, S.L., Gu, L.Q., Huang, Z.S., Design,synthesis and evaluation of isainditigotone derivates as acetylcho-linesterase and butyrylcholinesterase inhibitors (2008) Bioorg Med Chem Lett, 18, pp. 3790-3793
  • Vassar, R., Bennett, B.D., Babu-Khan, S., Beta-secretase cleavageof Alzheimer's amyloid precursor protein by the transmembraneaspartic protease BACE (1999) Science, 286, pp. 735-741
  • Yan, R., Bienkowski, M.J., Shuck, M.E., Membrane-anchoredaspartyl protease with Alzheimer's disease beta-secretase activity (1999) Nature, 402, pp. 533-537
  • Sinha, S., Anderson, J.P., Barbour, R., Purification and cloning ofamyloid precursor protein beta-secretase from human brain (1999) Nature, 402, pp. 537-540
  • Sinha, S., Lieberburg, I., Cellular mechanisms of beta-amyloid production and secretion (1999) Proc Natl Acad Sci USA, 9, pp. 11049-11053
  • Ghosh, A.K., Bilcer, G., Harwood, C., Structure-based design:Potent inhibitors of human brain memapsin 2 (beta-secretase) (2001) J Med Chem, 44, pp. 2865-2868
  • John, V., Beck, J.P., Bienkowski, M.J., Sinha, S., Heinrikson, R.L., Humanbeta-secretase (BACE) and BACE inhibitors (2003) J Med Chem, 46, pp. 4625-4630
  • Hong, L., Koelsch, G., Lin, X., Structure of the protease domainof memapsin 2(beta-secretase) complexed with inhibitor (2000) Science, 290, pp. 150-153
  • Ghosh, A.K., Shin, D., Downs, D., Design of potent inhibitors forhuman brain memapsin 2 (β-secretase) (2000) J Am Chem Soc, 122, pp. 3522-3523
  • Hong, L., Tang, J., Flap position of free memapsin 2 (beta-secretase),a model for flap opening in aspartic protease catalysis (2004) Biochemistry, 43, pp. 4689-4695
  • Patel, S., Vuillard, L., Cleasby, A., Murray, C.W., Yon, J., Apo andinhibitor complex structures of BACE (beta-secretase) (2004) J Mol Biol, 343, pp. 407-416
  • Shimizu, H., Tosaki, A., Kaneko, K., Hisano, T., Sakurai, T., Nukina, N., Crystal structure of an active form of BACE1, an enzyme resposible for amyloid beta protein production (2008) Mol Cell Biol, 28, pp. 3663-3971
  • Yu, N., Hayik, S.A., Wang, B., Liao, N., Reynolds, C.H., Merz Jr., K.M., Assigning the protonation states of the key aspartates in β-secretaseusing QM/MM X-ray structure refinement (2006) J Chem Theory Comput, 2, pp. 1057-1069
  • Polgár, T., Keserü, G.M., Virtual screening for β-secretase (BACE1)inhibitors reveals the importance of protonation states at Asp32 andAsp228 (2005) J Med Chem, 48, pp. 3749-3755
  • Park, H., Lee, S., Determination of the active site protonation state of-secretase from molecular dynamics simulation and docking experiment: Implications for structure-based inhibitor design (2003) J AmChem Soc, 125, pp. 16416-16422
  • Rajamani, R., Reynolds, C.H., Modeling the protonation states of thecatalytic aspartates in β-secretase (2004) J Med Chem, 47, pp. 5159-5166
  • Huang, D., Caflisch, A., Efficient evaluation of binding free energyusing continuum electrostatics solvation (2004) J Med Chem, 47, pp. 5791-5797
  • Murray, C.W., Callaghan, O., Chessari, G., Application of frag-ment screening by X-ray crystallography to beta-secretase (2007) J Med Chem, 50, pp. 1116-1123
  • Hanessian, S., Yun, H., Hou, Y., Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic andheterocyclic peptidomimetics (2005) J Med Chem, 48, pp. 5175-5190
  • Stachel, S.J., Coburn, C.A., Steele, T.G., Conformationally biasedP3 amide replacvement of beta-secretase inhibitors (2006) Bioorg Med Chem Lett, 16, pp. 641-644
  • Freslkos, J.N., Fobian, Y.M., Benson, T.E., Design of potentinhibitors of human beta-secretase. Part 2 (2007) Bioorg Med Chem Lett, 17, pp. 78-81
  • Turner III, R.T., Hong, L., Koelsch, G., Ghosh, A.K., Tang, J., Structurallocations and functional roles of new subsites S5, S6, and S7 inmemapsin 2 (beta-secretase) (2005) Biochemistry, 44, pp. 105-112
  • Hanessian, S., Yang, G., Rondeau, J.M., Neumann, U., Betschart C,Tintelnot-Blomley M. Structure-based design and synthesis of mac-roheterocyclic peptidomimetic inhibitors of the aspartic proteasebeta-site amyloid precursor protein cleaving enzyme (BACE) (2006) J Med Chem, 49, pp. 4544-4567
  • Coburn, C.A., Stachel, S.J., Li, Y.M., Identification of a smallmolecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases (2004) J Med Chem, 47, pp. 6117-6119
  • Stachel, S.J., Coburn, C.A., Steele, T.G., Structure-based design ofpotent and selective cell-permeable inhibitors of human beta-secretase (BACE-1) (2004) J Med Chem, 47, pp. 6447-6450
  • Congreve, M., Aharony, D., Albert, J., Application of fragmentscreening by X-ray crystallography to the discovery of aminopyri-dines as inhibitors of beta-secretase (2007) J Med Chem, 50, pp. 1124-1132
  • Edwards, P.D., Albert, J.S., Sylvester, M., Application of fragment-based lead generation to the discovery of novel, cyclicamidine beta-secretase inhibitors with nanomolar potency, cellularactivity, and high ligand efficiency (2007) J Med Chem, 50, pp. 5912-5925
  • Cole, D.C., Manas, E.S., Stock, J.R., Acylguanidines as small-moleculae b-secretase inhibitors (2006) J Med Chem, 49, pp. 6158-6161
  • Cole, D.C., Stock, J.R., Chopra, R., Acylguanidine inhibitors ofbeta-secretase: Optimization of the pyrrole ring substituents extend-ing into the S1 and S3 substrate binding pockets (2008) Bioorg MedChem Lett, 18, pp. 1063-1066
  • Malamas, M.S., Erdei, J., Gunawan, I., Aminoimidazoles aspotent and selective human beta-secretase (BACE1) inhibitors (2009) J Med Chem, 52, pp. 6314-6323
  • Malamas, M.S., Barnes, K., Johnson, M., Di-substituted pyridinylaminohydantoins as potent and highly selective human beta-secretase (BACE1) inhibitors (2010) Bioorg Med Chem, 18, pp. 630-639
  • Nowak, P., Cole, D.C., Aulabaugh, A., Discovery and initialoptimization of 5,5'-disubstituted aminohydantoins as potent beta-secretase (BACE1) inhibitors (2010) Bioorg Med Chem Lett, 20, pp. 632-635
  • Godemann, R., Madden, J., Krämer, J., Fragment-based discov-ery of BACE1 inhibitors using functional analysis (2009) Biochemistry, 48, pp. 10743-10751
  • Wang, Y.S., Strickland, C., Voigt, J.H., Application of fragment-based NMR screening, X-ray crystallography, structure-based de-sign, and focused chemical library design to identify novel μMleads for the development of nM BACE-1 (-site APP cleaving en-zyme 1) inhibitors (2010) J Med Chem, 53, pp. 942-950
  • Zhu, Z., Sun, Z.Y., Ye, Y., Discovery of cyclic acylguanidines ashighly potent and selective -site amyloid cleaving enzyme(BACE) inhibitors: Part I - Inhibitor design and validation (2010) J MedChem, 53, pp. 951-965

Citas:

---------- APA ----------
Galdeano, C., Viayna, E., Arroyo, P., Bidon-Chanal, A., Blas, J.R., Muñoz-Torrero, D. & Luque, F.J. (2010) . Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-alzheimer agents. Current Pharmaceutical Design, 16(25), 2818-2836.
http://dx.doi.org/10.2174/138161210793176536
---------- CHICAGO ----------
Galdeano, C., Viayna, E., Arroyo, P., Bidon-Chanal, A., Blas, J.R., Muñoz-Torrero, D., et al. "Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-alzheimer agents" . Current Pharmaceutical Design 16, no. 25 (2010) : 2818-2836.
http://dx.doi.org/10.2174/138161210793176536
---------- MLA ----------
Galdeano, C., Viayna, E., Arroyo, P., Bidon-Chanal, A., Blas, J.R., Muñoz-Torrero, D., et al. "Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-alzheimer agents" . Current Pharmaceutical Design, vol. 16, no. 25, 2010, pp. 2818-2836.
http://dx.doi.org/10.2174/138161210793176536
---------- VANCOUVER ----------
Galdeano, C., Viayna, E., Arroyo, P., Bidon-Chanal, A., Blas, J.R., Muñoz-Torrero, D., et al. Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-alzheimer agents. Curr. Pharm. Des. 2010;16(25):2818-2836.
http://dx.doi.org/10.2174/138161210793176536