E
Earl E. Clarke
Researcher at Merck & Co.
Publications - 20
Citations - 1966
Earl E. Clarke is an academic researcher from Merck & Co.. The author has contributed to research in topics: Binding site & Transition state analog. The author has an hindex of 16, co-authored 20 publications receiving 1909 citations. Previous affiliations of Earl E. Clarke include Merck Sharp & Dohme Federal Credit Union.
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Journal ArticleDOI
Involvement of Caspases in Proteolytic Cleavage of Alzheimer’s Amyloid-β Precursor Protein and Amyloidogenic Aβ Peptide Formation
François G. Gervais,Daigen Xu,George S. Robertson,John P. Vaillancourt,Yanxia Zhu,JingQi Huang,Andréa C. LeBlanc,Smith David W,Michael Rigby,Mark S. Shearman,Earl E. Clarke,Hui Zheng,Leonardus H. T. Van Der Ploeg,Salvatore C. Ruffolo,Nancy A. Thornberry,Steve Xanthoudakis,Robert Zamboni,Sophie Roy,Donald W. Nicholson +18 more
TL;DR: Caspases appear to play a dual role in proteolytic processing of APP and the resulting propensity for Aβ peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.
Journal ArticleDOI
L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity.
Mark S. Shearman,Dirk Beher,Earl E. Clarke,Huw D. Lewis,Timothy Harrison,Peter W. Hunt,Alan Nadin,Adrian L. Smith,Graeme Irvine Stevenson,José L. Castro +9 more
TL;DR: The identification of L-685,458 is reported as a structurally novel inhibitor of AβPP γ-secretase activity, with a similar potency for Alzheimer's disease targeting the N- and C-termini of the Aβ peptide.
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Selected Non-steroidal Anti-inflammatory Drugs and Their Derivatives Target γ-Secretase at a Novel Site EVIDENCE FOR AN ALLOSTERIC MECHANISM
Dirk Beher,Earl E. Clarke,Jonathan D.J. Wrigley,Agnes C.L. Martin,Alan Nadin,Ian Churcher,Mark S. Shearman +6 more
TL;DR: It is demonstrated that in cell-free systems the mode of action of selected NSAIDs and their derivatives, depending on the concentrations used, can either be classified as modulatory or inhibitory.
Journal ArticleDOI
In Vitro Characterization of the Presenilin-Dependent γ-Secretase Complex Using a Novel Affinity Ligand
Dirk Beher,Michael Fricker,Alan Nadin,Earl E. Clarke,Jonathan D.J. Wrigley,Yue-Ming Li,Janetta G. Culvenor,Colin L. Masters,Timothy Harrison,Mark S. Shearman +9 more
TL;DR: A novel biotinylated affinity ligand which is based on a specific inhibitor containing a hydroxyethylene dipeptide isostere, known to serve as a transition state analogue for aspartic proteinases is developed and confirmed the presence of the presenilin heterodimer and mature nicastrin in the active enzyme complex.
Journal ArticleDOI
4-Substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors
Ian Churcher,Dirk Beher,Jonathan D. Best,José L. Castro,Earl E. Clarke,Amy Gentry,Timothy Harrison,Laure Hitzel,Euan R. Kay,Sonia Kerrad,Huw D. Lewis,Pablo Morentin-Gutierrez,Russell J. Mortishire-Smith,Paul Joseph Oakley,Michael Reilly,Duncan Shaw,Mark S. Shearman,Martin Richard Teall,Susie Williams,Jonathan D.J. Wrigley +19 more
TL;DR: A further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o.in APP-YAC mice).