Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase.

To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC(50)=0.567 microM; AChE: IC(50)=1.83 microM), and also showed excellent inhibitory effects on Abeta production of APP transfected HEK293 cells (IC(50)=98.7 nM) and mild protective effect against hydrogen peroxide (H(2)O(2))-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Abeta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.

[1]  K. Gulya,et al.  The cholinergic system in Alzheimer's disease , 1997, Progress in Neurobiology.

[2]  Maurizio Recanatini,et al.  Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease. , 2007, Journal of medicinal chemistry.

[3]  Hong-yu Zhang,et al.  A new strategy to combat Alzheimer's disease. Combining radical-scavenging potential with metal-protein-attenuating ability in one molecule. , 2005, Bioorganic & medicinal chemistry letters.

[4]  Heather B. Miller,et al.  Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. , 2008, Bioorganic & medicinal chemistry letters.

[5]  M. Katharine Holloway,et al.  BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres , 2006 .

[6]  H. Sugimoto,et al.  Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives. , 1992, Journal of medicinal chemistry.

[7]  Xin Wang,et al.  Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based non-peptide beta-secretase (BACE) inhibitors. , 2006, Bioorganic & medicinal chemistry.

[8]  R. León,et al.  Synthesis and biological evaluation of new 4H-pyrano[2,3-b]quinoline derivatives that block acetylcholinesterase and cell calcium signals, and cause neuroprotection against calcium overload and free radicals. , 2006, European journal of medicinal chemistry.

[9]  A. Stamford,et al.  Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[10]  V. Andrisano,et al.  Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties. , 2004, Journal of medicinal chemistry.

[11]  Maurizio Recanatini,et al.  Multi-target-directed ligands to combat neurodegenerative diseases. , 2008, Journal of medicinal chemistry.

[12]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[13]  A. Cavalli,et al.  3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer's disease therapy. , 2003, Journal of medicinal chemistry.

[14]  T Nakamura,et al.  Novel piperidine derivatives. Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives. , 1990, Journal of medicinal chemistry.

[15]  H. Schugar,et al.  Synthesis, characterization, and metal coordinating ability of multifunctional carbohydrate-containing compounds for Alzheimer's therapy. , 2007, Journal of the American Chemical Society.

[16]  D. Rotella.  Stereoselective synthesis of erythro α-amino epoxides , 1995 .

[17]  Junya Qu,et al.  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. , 2007, Journal of medicinal chemistry.

[18]  S. Dei,et al.  The medicinal chemistry of Alzheimer's and Alzheimer-like diseases with emphasis on the cholinergic hypothesis. , 1995, Farmaco.

[19]  U. Holzgrabe,et al.  Search for dual function inhibitors for Alzheimer's disease: synthesis and biological activity of acetylcholinesterase inhibitors of pyridinium-type and their Abeta fibril formation inhibition capacity. , 2006, Bioorganic & medicinal chemistry.

[20]  Rui Wang,et al.  Huperzine A attenuates hydrogen peroxide-induced apoptosis by regulating expression of apoptosis-related genes in rat PC12 cells , 2001, Neuroreport.

[21]  M. Katharine Holloway,et al.  Macrocyclic Inhibitors of β-Secretase: Functional Activity in an Animal Model. , 2006 .

[22]  Maurizio Recanatini,et al.  A small molecule targeting the multifactorial nature of Alzheimer's disease. , 2007, Angewandte Chemie.

[23]  H. Cai,et al.  BACE1 is the major β-secretase for generation of Aβ peptides by neurons , 2001, Nature Neuroscience.

[24]  R A Mueller,et al.  Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. , 1993, Journal of medicinal chemistry.

[25]  T. Aoyagi,et al.  Synthesis and structure-activity relationships of bestatin analogues, inhibitors of aminopeptidase B. , 1977, Journal of medicinal chemistry.

[26]  C. Wermuth,et al.  Design, synthesis, and structure-activity relationships of a series of 3-[2-(1-benzylpiperidin-4-yl)ethylamino]pyridazine derivatives as acetylcholinesterase inhibitors. , 2001, Journal of medicinal chemistry.

[27]  A. Cavalli,et al.  Synthesis and screening for antiacetylcholinesterase activity of (1-benzyl-4-oxopiperidin-3-ylidene)methylindoles and -pyrroles related to donepezil. , 2001, Journal of medicinal chemistry.

[28]  Jian Sun,et al.  Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1. , 2006, Journal of medicinal chemistry.

[29]  Y. Kiso,et al.  Design and synthesis of highly active Alzheimer's beta-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability. , 2005, Bioorganic & medicinal chemistry letters.

[30]  Jerry J Buccafusco,et al.  Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. , 2005, Trends in pharmacological sciences.

[31]  B. Szabó,et al.  KMI-008, a novel beta-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: design and synthesis of substrate-based octapeptides. , 2003, Bioorganic & medicinal chemistry letters.

[32]  A. Maggi,et al.  NEW ACETYLCHOLINESTERASE INHIBITORS , 1997 .

[33]  Joseph B. Moon,et al.  Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase. , 2007, Journal of medicinal chemistry.

[34]  F. J. Luque,et al.  Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. , 2005, Journal of medicinal chemistry.

[35]  S. Kitazume,et al.  KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine. , 2004, Bioorganic & medicinal chemistry letters.

[36]  P. Carrupt,et al.  Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase. , 2001, Journal of medicinal chemistry.

[37]  M. Sasaki,et al.  Novel acetylcholinesterase inhibitor as increasing agent on rhythmic bladder contractions: SAR of 8-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (TAK-802) and related compounds. , 2005, Bioorganic & medicinal chemistry.

[38]  José Marco-Contelles,et al.  Novel multipotent tacrine-dihydropyridine hybrids with improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of Alzheimer's disease. , 2006, Journal of medicinal chemistry.

[39]  A. Cavalli,et al.  Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. , 2008, Bioorganic & medicinal chemistry letters.

[40]  Joel L. Sussman,et al.  Three-dimensional structure of a complex of E2020 with acetylcholinesterase from Torpedo californica , 1998, Journal of Physiology-Paris.

[41]  W R Markesbery,et al.  Oxidative stress hypothesis in Alzheimer's disease. , 1997, Free radical biology & medicine.

[42]  David S. Goodsell,et al.  A semiempirical free energy force field with charge‐based desolvation , 2007, J. Comput. Chem..

[43]  Joseph B. Moon,et al.  Design and Synthesis of Hydroxyethylene-Based Peptidomimetic Inhibitors of Human β-Secretase , 2004 .

[44]  J. Sussman,et al.  Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. , 1999, Structure.

[45]  V. Andrisano,et al.  Propidium-based polyamine ligands as potent inhibitors of acetylcholinesterase and acetylcholinesterase-induced amyloid-beta aggregation. , 2005, Journal of medicinal chemistry.

[46]  J. Randolph,et al.  Peptidomimetic inhibitors of HIV protease. , 2004, Current topics in medicinal chemistry.

[47]  Min Xu,et al.  Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1). , 2006, Journal of medicinal chemistry.

[48]  C. Behl,et al.  Hydrogen peroxide mediates amyloid β protein toxicity , 1994, Cell.

[49]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[50]  A. Cavalli,et al.  Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and nitrogen atoms of caproctamine. , 2003, Journal of medicinal chemistry.

[51]  C. Wermuth,et al.  Aminopyridazines as acetylcholinesterase inhibitors. , 1999, Journal of medicinal chemistry.

[52]  Alison R. Gregro,et al.  Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). , 2004, Journal of medicinal chemistry.

[53]  K. Appelt,et al.  Isophthalic acid derivatives: amino acid surrogates for the inhibition of HIV-1 protease , 1995 .

[54]  Wei Huang,et al.  Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease. , 2002, Journal of medicinal chemistry.

[55]  I. Lieberburg,et al.  Cellular mechanisms of beta-amyloid production and secretion. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Lin Hong,et al.  Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. , 2007, Journal of medicinal chemistry.

[57]  H. Schugar,et al.  Combating Alzheimer's disease with multifunctional molecules designed for metal passivation. , 2007, Angewandte Chemie.

[58]  Dongwoo Shin,et al.  Design of Potent Inhibitors for Human Brain Memapsin 2 (β-Secretase). , 2000, Journal of the American Chemical Society.

[59]  G. Perry,et al.  Therapeutic opportunities in Alzheimer disease: one for all or all for one? , 2005, Current medicinal chemistry.

[60]  A. Palmer,et al.  3,5-Disubstituted-4-hydroxyphenyls Linked to 3-Hydroxy-2-methyl- 4(1H)-pyridinone: Potent Inhibitors of Lipid Peroxidation and Cell Toxicity , 2000 .

[61]  Chi‐Huey Wong,et al.  Development of selective tight-binding inhibitors of leukotriene A4 hydrolase. , 1993, Journal of medicinal chemistry.

[62]  B Testa,et al.  Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs. , 2000, Journal of medicinal chemistry.

[63]  A. Cavalli,et al.  Cholinesterase inhibitors: xanthostigmine derivatives blocking the acetylcholinesterase-induced beta-amyloid aggregation. , 2005, Journal of medicinal chemistry.

[64]  W. Richards,et al.  Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation , 2001, Nature Neuroscience.

[65]  Vincenza Andrisano,et al.  Rational approach to discover multipotent anti-Alzheimer drugs. , 2005, Journal of medicinal chemistry.

[66]  G. Marshall,et al.  Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes. , 1991, Journal of medicinal chemistry.

[67]  T. Guo,et al.  Development of BACE1 inhibitors for Alzheimer's disease. , 2006, Current medicinal chemistry.

[68]  Maurizio Recanatini,et al.  Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease. , 2007, Journal of medicinal chemistry.

[69]  C. Pérez,et al.  Design and synthesis of N-benzylpiperidine-purine derivatives as new dual inhibitors of acetyl- and butyrylcholinesterase. , 2005, Bioorganic & medicinal chemistry.

[70]  S. Marumoto,et al.  Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter targeting potential agents for Alzheimer's disease. , 2002, Organic letters.

[71]  M L Bolognesi,et al.  Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer's disease. , 1998, Journal of medicinal chemistry.

[72]  C. Luo,et al.  Synthesis and evaluation of tacrine-E2020 hybrids as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease. , 2004, Bioorganic & medicinal chemistry letters.

[73]  Qi Zhang,et al.  Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor. , 2008, Bioorganic & medicinal chemistry letters.

[74]  M. Menziani,et al.  Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands. development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties. , 2005, Journal of medicinal chemistry.

[75]  Arun K. Ghosh,et al.  Structure-Based Design: Potent Inhibitors of Human Brain Memapsin 2 (β-Secretase) , 2001 .

[76]  L Hong,et al.  Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. , 2000, Science.

[77]  C. Pérez,et al.  Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. , 2006, Journal of medicinal chemistry.