D Beher

Summary

Affiliation: Merck Research Laboratories
Country: USA

Publications

  1. ncbi Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology
    D Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    J Biol Chem 276:45394-402. 2001
  2. ncbi Protease inhibitors as potential disease-modifying therapeutics for Alzheimer's disease
    Dirk Beher
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    Expert Opin Investig Drugs 14:1385-409. 2005
  3. ncbi Generation of C-terminally truncated amyloid-beta peptides is dependent on gamma-secretase activity
    Dirk Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK
    J Neurochem 82:563-75. 2002
  4. ncbi Gamma-secretase inhibition
    D Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    Biochem Soc Trans 30:534-7. 2002
  5. ncbi Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism
    Dirk Beher
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    J Biol Chem 279:43419-26. 2004
  6. ncbi In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand
    Dirk Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    Biochemistry 42:8133-42. 2003
  7. ncbi L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity
    M S Shearman
    Department of Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, England
    Biochemistry 39:8698-704. 2000
  8. ncbi Determination of guinea-pig cortical gamma-secretase activity ex vivo following the systemic administration of a gamma-secretase inhibitor
    S Grimwood
    Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Neuropharmacology 48:1002-11. 2005
  9. ncbi Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders
    N J Brandon
    Merck Sharp and Dohme, The Neuroscience Research Centre, Harlow, Essex, CM20 2QR, UK
    Mol Cell Neurosci 25:42-55. 2004
  10. ncbi Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia
    H Lewis
    Department of Molecular and Cellular Neuroscience, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Essex
    Neuropathol Appl Neurobiol 32:103-18. 2006

Collaborators

Detail Information

Publications32

  1. ncbi Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology
    D Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    J Biol Chem 276:45394-402. 2001
    ..Even though the beta-amyloid precursor protein cleavage and the S3 cleavage of the Notch receptor are inhibited by CBAP, an impairment of Trk receptor maturation was not observed...
  2. ncbi Protease inhibitors as potential disease-modifying therapeutics for Alzheimer's disease
    Dirk Beher
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    Expert Opin Investig Drugs 14:1385-409. 2005
    ..The outcomes of such trials will provide new directions to the scientific community and hopefully new treatment options for AD patients...
  3. ncbi Generation of C-terminally truncated amyloid-beta peptides is dependent on gamma-secretase activity
    Dirk Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK
    J Neurochem 82:563-75. 2002
    ....
  4. ncbi Gamma-secretase inhibition
    D Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    Biochem Soc Trans 30:534-7. 2002
    ....
  5. ncbi Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism
    Dirk Beher
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    J Biol Chem 279:43419-26. 2004
    ....
  6. ncbi In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand
    Dirk Beher
    Department of Biochemistry and Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    Biochemistry 42:8133-42. 2003
    ..This was also reflected by a co-distribution of both enzyme activities in subcellular fractions enriched for trans-Golgi network membranes...
  7. ncbi L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity
    M S Shearman
    Department of Molecular Biology, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, England
    Biochemistry 39:8698-704. 2000
    ..Specific and potent inhibitors of A beta PP gamma-secretase activity such as L-685,458 will enable important advances toward the identification and elucidation of the mechanism of action of this enigmatic protease...
  8. ncbi Determination of guinea-pig cortical gamma-secretase activity ex vivo following the systemic administration of a gamma-secretase inhibitor
    S Grimwood
    Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Neuropharmacology 48:1002-11. 2005
    ....
  9. ncbi Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders
    N J Brandon
    Merck Sharp and Dohme, The Neuroscience Research Centre, Harlow, Essex, CM20 2QR, UK
    Mol Cell Neurosci 25:42-55. 2004
    ....
  10. ncbi Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia
    H Lewis
    Department of Molecular and Cellular Neuroscience, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Essex
    Neuropathol Appl Neurobiol 32:103-18. 2006
    ..Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age...
  11. ncbi Cyclic sulfamide gamma-secretase inhibitors
    Tim Sparey
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 15:4212-6. 2005
    ..One compound with subnanomolar activity elicited a reduction in brain Abeta40 after oral dosing in APP-YAC mice...
  12. ncbi Gamma-secretase as a therapeutic target for the treatment of Alzheimer's disease
    Ian Churcher
    Department of Medicinal Chemistry, Merck Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK
    Curr Pharm Des 11:3363-82. 2005
    ..In this review we describe the literature regarding the discovery of the nature of gamma-secretase, the development of small molecule inhibitors and their in vivo profiles...
  13. ncbi Selective modulation of Abeta42 production in Alzheimer's disease: non-steroidal anti-inflammatory drugs and beyond
    Stefanie Leuchtenberger
    Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
    Curr Pharm Des 12:4337-55. 2006
    ..Hopes are high that in the near future this will lead to the development of clinically viable compounds which selectively target Abeta42 as a key molecule in the pathogenesis of AD...
  14. ncbi 4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors
    Ian Churcher
    Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 16:280-4. 2006
    ..g., compound 32, MED 1mg/kg p.o. in APP-YAC mice)...
  15. ncbi C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation
    Jun Wang
    Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurochem 96:218-27. 2006
    ..Together, these observations strongly support the hypothesis that the PAL motif contributes to the active site conformation of gamma-secretase and of SPP...
  16. ncbi The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent
    Nicholas Stock
    Department of Chemistry, Merck Research Laboratories, 3535 General Atomics Ct, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 16:2219-23. 2006
    ....
  17. pmc LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease
    John Majercak
    Department of Alzheimer s Research, Merck and Co, Inc, West Point, PA 19486, USA
    Proc Natl Acad Sci U S A 103:17967-72. 2006
    ..Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target...
  18. ncbi Intra- or intercomplex binding to the gamma-secretase enzyme. A model to differentiate inhibitor classes
    Earl E Clarke
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    J Biol Chem 281:31279-89. 2006
    ..This finding suggests that non-steroidal anti-inflammatory drug-type gamma-secretase modulators target an alternative site on the enzyme, thereby changing the conformation of the binding sites for gamma-secretase inhibitors...
  19. ncbi 3-Substituted gem-cyclohexane sulfone based gamma-secretase inhibitors for Alzheimer's disease: conformational analysis and biological activity
    Richard A Jelley
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 16:3839-42. 2006
    ..Recently chemistry has been directed towards the 3-position and substitution here has also provided compounds with high gamma-secretase activity...
  20. ncbi Functional overexpression of gamma-secretase reveals protease-independent trafficking functions and a critical role of lipids for protease activity
    Jonathan D J Wrigley
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    J Biol Chem 280:12523-35. 2005
    ..Furthermore, these data show that it is important to discriminate between intact, inactive gamma-secretase complexes and the active form of the enzyme, indicating the care that must be taken in the study of gamma-secretase...
  21. pmc The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain
    Stefan F Lichtenthaler
    Massachusetts General Hospital Harvard Medical School, Wellman Building, 50 Blossom Street, Boston, MA 02114, USA
    Proc Natl Acad Sci U S A 99:1365-70. 2002
    ..One cleavage site was located around the middle of the TMD, regardless of its actual length. An additional cleavage occurred within the N-terminal half of their TMD and thus at the opposite side of the Notch cleavage site...
  22. ncbi gamma-Secretase cleavage site specificity differs for intracellular and secretory amyloid beta
    Heike S Grimm
    Center for Molecular Biology Heidelberg ZMBH, University of Heidelberg, Im Neuenheimer Feld 282, D 69120 Heidelberg, Germany
    J Biol Chem 278:13077-85. 2003
    ....
  23. ncbi Design and synthesis of highly potent benzodiazepine gamma-secretase inhibitors: preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by use of a
    Ian Churcher
    Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
    J Med Chem 46:2275-8. 2003
    ..06 nM). 34 could also be selectively methylated to give [(3)H]-28, which is of use in radioligand binding assays...
  24. ncbi gamma-Secretase inhibitors--from molecular probes to new therapeutics?
    Timothy Harrison
    Merck Sharp and Dohme Research Laboratories, Department of Medicinal Chemistry, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Prog Med Chem 41:99-127. 2003
  25. ncbi Novel aspects of accumulation dynamics and A beta composition in transgenic models of AD
    Huw D Lewis
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    Neurobiol Aging 25:1175-85. 2004
    ..Application of the same extraction and quantitation procedures to samples of temporal cortex from AD sufferers indicates however that A beta(40) is only a minor component of beta-amyloid in humans...
  26. ncbi Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding
    Jonathan D J Wrigley
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK
    J Neurochem 90:1312-20. 2004
    ..Together, these data further incriminate the region around the intramembranous aspartates as the active site of the enzyme, targeted by transition state analogue inhibitors, and highlight the roles of individual residues...
  27. ncbi Fatty acids increase presenilin-1 levels and [gamma]-secretase activity in PSwt-1 cells
    Yanzhu Liu
    Department of Medicine, Columbia University, New York, NY, USA
    J Lipid Res 45:2368-76. 2004
    ..Nontransfected human neuroblastoma cells also showed increased presenilin when cultured in 0.4 mM OA. Lipids may be important biological determinants of PS1 level and gamma-secretase activity...
  28. ncbi gamma-Secretase as a target for drug intervention in Alzheimer's disease
    Timothy Harrison
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow Essex CM20 2QR, UK
    Curr Opin Drug Discov Devel 7:709-19. 2004
    ..In this review, progress in the development of small-molecule inhibitors will be described, and potential toxicity issues associated with the development of gamma-secretase inhibitors discussed...
  29. ncbi Gamma-secretase complex assembly within the early secretory pathway
    Anja Capell
    Adolf Butenandt Institut, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians Universitat, Schillerstrasse 44, 80336 Munich, Germany
    J Biol Chem 280:6471-8. 2005
    ....
  30. ncbi A novel series of potent gamma-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core
    Stephen J Lewis
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 15:373-8. 2005
    ..2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated...
  31. ncbi Gamma-secretase modulation and its promise for Alzheimer's disease: a rationale for drug discovery
    Dirk Beher
    Amgen Inc, Department of Neuroscience, One Amgen Center Drive, Thousand Oaks, CA 91320, USA
    Curr Top Med Chem 8:34-7. 2008
    ....
  32. ncbi Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling
    Huw D Lewis
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, UK
    Chem Biol 14:209-19. 2007
    ..Together, these data strengthen the rationale for using gamma-secretase inhibitors therapeutically and suggest that programmed cell death may contribute to reduction of tumor burden in the clinic...