Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.
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.
Dovey
H F
HF
Elan Pharmaceuticals, Inc., South San Francisco, CA 94080, USA.
John
V
V
Anderson
J P
JP
Chen
L Z
LZ
de Saint Andrieu
P
P
Fang
L Y
LY
Freedman
S B
SB
Folmer
B
B
Goldbach
E
E
Holsztynska
E J
EJ
Hu
K L
KL
Johnson-Wood
K L
KL
Kennedy
S L
SL
Kholodenko
D
D
Knops
J E
JE
Latimer
L H
LH
Lee
M
M
Liao
Z
Z
Lieberburg
I M
IM
Motter
R N
RN
Mutter
L C
LC
Nietz
J
J
Quinn
K P
KP
Sacchi
K L
KL
Seubert
P A
PA
Shopp
G M
GM
Thorsett
E D
ED
Tung
J S
JS
Wu
J
J
Yang
S
S
Yin
C T
CT
Schenk
D B
DB
May
P C
PC
Altstiel
L D
LD
Bender
M H
MH
Boggs
L N
LN
Britton
T C
TC
Clemens
J C
JC
Czilli
D L
DL
Dieckman-McGinty
D K
DK
Droste
J J
JJ
Fuson
K S
KS
Gitter
B D
BD
Hyslop
P A
PA
Johnstone
E M
EM
Li
W Y
WY
Little
S P
SP
Mabry
T E
TE
Miller
F D
FD
Audia
J E
JE
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004151:Dipeptides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004151:Dipeptides; D004791:Enzyme Inhibitors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse