Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain

  • J Neurochem. 2001 Jan;76(1):173-81. doi: 10.1046/j.1471-4159.2001.00012.x.
H F Dovey  1 ,  V John ,  J P Anderson ,  L Z Chen ,  P de Saint Andrieu ,  L Y Fang ,  S B Freedman ,  B Folmer ,  E Goldbach ,  E J Holsztynska ,  K L Hu ,  K L Johnson-Wood ,  S L Kennedy ,  D Kholodenko ,  J E Knops ,  L H Latimer ,  M Lee ,  Z Liao ,  I M Lieberburg ,  R N Motter ,  L C Mutter ,  J Nietz ,  K P Quinn ,  K L Sacchi ,  P A Seubert ,  G M Shopp ,  E D Thorsett ,  J S Tung ,  J Wu ,  S Yang ,  C T Yin ,  D B Schenk ,  P C May ,  L D Altstiel ,  M H Bender ,  L N Boggs ,  T C Britton ,  J C Clemens ,  D L Czilli ,  D K Dieckman-McGinty ,  J J Droste ,  K S Fuson ,  B D Gitter ,  P A Hyslop ,  E M Johnstone ,  W Y Li ,  S P Little ,  T E Mabry ,  F D Miller ,  J E Audia
Affiliations
  • 1. Elan Pharmaceuticals, Inc., South San Francisco, CA 94080, USA.
PMID: 11145990 DOI: 10.1046/j.1471-4159.2001.00012.x
Abstract

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's Disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's Disease.

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