Ishrut Hussain

Summary

Affiliation: GlaxoSmithKline Research and Development
Country: USA

Publications

  1. ncbi request reprint Characterization of the ectodomain shedding of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)
    Ishrut Hussain
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom
    J Biol Chem 278:36264-8. 2003
  2. ncbi request reprint Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo
    Ishrut Hussain
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, Harlow, Essex, UK
    J Neurochem 100:802-9. 2007
  3. ncbi request reprint The potential for BACE1 inhibitors in the treatment of Alzheimer's disease
    Ishrut Hussain
    GlaxoSmithKline Research and Development Ltd, Neurodegeneration Research Neurology and GI Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW UK
    IDrugs 7:653-8. 2004
  4. doi request reprint Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent
    Nicolas Charrier
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 19:3669-73. 2009
  5. doi request reprint Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics
    Nicolas Charrier
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 19:3664-8. 2009
  6. doi request reprint BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs)
    Brian Clarke
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 18:1011-6. 2008
  7. doi request reprint BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296
    Brian Clarke
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Harlow, Essex, UK
    Bioorg Med Chem Lett 20:4639-44. 2010
  8. doi request reprint Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics
    Nicolas Charrier
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 19:3674-8. 2009
  9. doi request reprint BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells
    Paul Beswick
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
    Bioorg Med Chem Lett 18:1022-6. 2008
  10. doi request reprint Dynamics of Aβ42 reduction in plasma, CSF and brain of rats treated with the γ-secretase modulator, GSM-10h
    Julie Hawkins
    Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, New Frontiers Science Park, Harlow, UK
    Neurodegener Dis 8:455-64. 2011

Collaborators

Detail Information

Publications20

  1. ncbi request reprint Characterization of the ectodomain shedding of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)
    Ishrut Hussain
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom
    J Biol Chem 278:36264-8. 2003
    ..In addition, we show that the BACE1 sheddase is distinct from alpha-secretase and, importantly, that inhibition of BACE1 shedding does not influence amyloid precursor protein processing at the beta-site...
  2. ncbi request reprint Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo
    Ishrut Hussain
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, Harlow, Essex, UK
    J Neurochem 100:802-9. 2007
    ..This pivotal first report of central Abeta lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease...
  3. ncbi request reprint The potential for BACE1 inhibitors in the treatment of Alzheimer's disease
    Ishrut Hussain
    GlaxoSmithKline Research and Development Ltd, Neurodegeneration Research Neurology and GI Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW UK
    IDrugs 7:653-8. 2004
    ..Due to its pivotal role in A beta production, many pharmaceutical companies are actively pursuing the challenging task of developing BACE1 inhibitors for evaluation in the clinic...
  4. doi request reprint Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent
    Nicolas Charrier
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 19:3669-73. 2009
    ..This Letter describes the discovery of such inhibitors...
  5. doi request reprint Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics
    Nicolas Charrier
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 19:3664-8. 2009
    ..In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies...
  6. doi request reprint BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs)
    Brian Clarke
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 18:1011-6. 2008
    ..These inhibitors were capable of lowering amyloid production in a cell-based assay...
  7. doi request reprint BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296
    Brian Clarke
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Harlow, Essex, UK
    Bioorg Med Chem Lett 20:4639-44. 2010
    ..These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296...
  8. doi request reprint Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics
    Nicolas Charrier
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 19:3674-8. 2009
    ..In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration...
  9. doi request reprint BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells
    Paul Beswick
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
    Bioorg Med Chem Lett 18:1022-6. 2008
    ..Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays...
  10. doi request reprint Dynamics of Aβ42 reduction in plasma, CSF and brain of rats treated with the γ-secretase modulator, GSM-10h
    Julie Hawkins
    Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, New Frontiers Science Park, Harlow, UK
    Neurodegener Dis 8:455-64. 2011
    ..We recently identified a novel γ-secretase modulator, GSM-10h, which effectively lowers Aβ42 production in cells and in amyloid precursor protein transgenic mice...
  11. doi request reprint Second generation of hydroxyethylamine BACE-1 inhibitors: optimizing potency and oral bioavailability
    Nicolas Charrier
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Park, Harlow, Essex, UK
    J Med Chem 51:3313-7. 2008
    ..Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable...
  12. doi request reprint BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character
    Brian Clarke
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
    Bioorg Med Chem Lett 18:1017-21. 2008
    ..Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures...
  13. doi request reprint TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to γ-secretase modulation and amyloid-β₄₂ lowering by GSM-10h
    Ishrut Hussain
    Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, Harlow, UK
    Neurodegener Dis 8:15-24. 2011
    ..Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aβ₄₂ peptide while avoiding deleterious activity on Notch processing...
  14. ncbi request reprint APP transgenic mouse models and their use in drug discovery to evaluate amyloid- lowering therapeutics
    Ishrut Hussain
    Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, New Frontiers Science Park, Harlow, Essex, UK
    CNS Neurol Disord Drug Targets 9:395-402. 2010
    ..This review highlights how APP transgenic mouse models have successfully been used in drug discovery to support the progression of A lowering therapeutics to clinical trials to ultimately test the 'amyloid hypothesis' of AD...
  15. doi request reprint Piperidine-derived gamma-secretase modulators
    Adrian Hall
    Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
    Bioorg Med Chem Lett 20:1306-11. 2010
    ..Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse...
  16. ncbi request reprint BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper
    Barbara Angeletti
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom
    J Biol Chem 280:17930-7. 2005
    ..Finally, we demonstrate that the twenty-four residue C-terminal domain of BACE1 binds a single Cu(I) atom with high affinity through cysteine residues...
  17. doi request reprint Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition
    Kerry A Waters
    Schizophrenia and Cognitive Disorders Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK
    Behav Brain Res 228:211-8. 2012
    ..These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia...
  18. pmc Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein
    Edward T Parkin
    Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom
    Proc Natl Acad Sci U S A 104:11062-7. 2007
    ..In conclusion, this is a mechanism by which the cellular production of the neurotoxic Abeta is regulated by PrP(C) and may have implications for both Alzheimer's and prion diseases...
  19. pmc Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein
    Joanna M Cordy
    Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
    Proc Natl Acad Sci U S A 100:11735-40. 2003
    ..Changes in the local membrane environment during aging may facilitate the cosegregation of APP and BACE leading to increased beta-amyloid production...
  20. ncbi request reprint Emerging therapeutics for Alzheimer's disease
    Emma R L C Vardy
    University of Leeds, Academic Unit of Molecular Vascular Medicine, Leeds Institute of Genetics, Health and Therapeutics, Clarendon Way, Leeds LS2 9JT, UK
    Expert Rev Neurother 6:695-704. 2006
    ..Each of these will be considered, in detail, in terms of the variety of therapeutic approaches currently being investigated and mechanisms that may prove amenable to intervention in the future...