Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease

Neurology

Volumn 66, Issue 4, 2006, Pages 602-604

  Siemers, E R ^a   Quinn, J F ^b   Kaye, J ^b   Farlow, M R ^c   Porsteinsson, A ^d   Tariot, P ^d   Zoulnouni, P ^e   Galvin, J E ^f   Holtzman, D M ^f   Knopman, D S ^g   Satterwhite, J ^a   Gonzales, C ^a   Dean, R A ^a   May, P C ^a  

^a ELI LILLY AND COMPANY   (United States)

^b OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^c INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF ROCHESTER MEDICAL CENTER   (United States)

^e CALIFORNIA CLINICAL TRIALS   (United States)

^f WASHINGTON UNIVERSITY   (United States)

^g MAYO CLINIC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN[1-40]; GAMMA SECRETASE INHIBITOR; LY 450139; UNCLASSIFIED DRUG; ALANINE; ASPARTIC PROTEINASE; AZEPINE DERIVATIVE; BACE1 PROTEIN, HUMAN; DRUG DERIVATIVE; ENZYME INHIBITOR; N2 ((2S) 2 (3,5 DIFLUOROPHENYL) 2 HYDROXYETHANOYL) N1 ((7S) 5 METHYL 6 OXO 6,7 DIHYDRO 5H DIBENZO(B,D)AZEPIN 7 YL) L ALANINAMIDE; N2-((2S)-2-(3,5-DIFLUOROPHENYL)-2-HYDROXYETHANOYL)-N1-((7S)-5-METHYL-6-OXO-6,7-DIHYDRO-5H-DIBENZO(B,D)AZEPIN-7-YL)-L-ALANINAMIDE; PLACEBO; PROTEINASE; SECRETASE;

ALZHEIMER DISEASE; ARTICLE; BARRETT ESOPHAGUS; CEREBROSPINAL FLUID; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOSE RESPONSE; DRUG MEGADOSE; DRUG TOLERABILITY; GASTROINTESTINAL HEMORRHAGE; HUMAN; MAJOR CLINICAL STUDY; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; RANDOMIZED CONTROLLED TRIAL; COMPARATIVE STUDY; METABOLISM;

ALANINE; ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ENDOPEPTIDASES; AZEPINES; ENDOPEPTIDASES; ENZYME INHIBITORS; HUMANS; PLACEBOS;

EID: 33645013015     PISSN: 00283878     EISSN: None     Source Type: Journal    
DOI: 10.1212/01.WNL.0000198762.41312.E1     Document Type: Article

References (10)

1. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics [published correction appears in Science 2002;297:2209]. Science 2002;297:353-356.
2. Holtzman DM. Role of apoe/Abeta interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. J Mol Neurosci 2001;17:147-155.
3. Gitter BD, Czilli DL, Li W, Dieckman DK, et al. Stereoselective inhibition of amyloid beta peptide secretion by LY450139 dihydrate, a novel functional gamma secretase inhibitor. Neurobiol Aging 2004;25 (suppl 2):571.
4. May PC, Yang Z, Li W, et al. Multi-compartmental pharmaco-dynamic assessment of the functional gamma-secretase inhibitor LY450139 dihydrate in PDAPP transgenic mice and non-transgenic mice. Neurobiol Aging 2004;25 (suppl 25):65.
5. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995;373:523-527.
6. Siemers E, Skinner M, Dean RA, et al. Safety, tolerability and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28:126-132.
7. Ness DK, Boggs LN, Hepburn DL, et al. Reduced β-amyloid burden, increased C-99 concentrations and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate dihydrate daily by gavage for 5 months. Neurobiol Aging 2004;25 (suppl 2):238.
8. Micchelli CA, Esler WP, Kimberly WT, et al. Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila. FASEB J 2003;17:79-81.
9. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math 1 for secretory cell lineage commitment in the mouse intestine. Science 2001;294:2155-2158.
10. Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits Aβ production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004;279:12876-12882.