A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease.
We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.
Fukumoto
Hiroaki
H
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan. Fukumoto_Hiroaki@takeda.co.jp
Takahashi
Hideki
H
Tarui
Naoki
N
Matsui
Junji
J
Tomita
Taisuke
T
Hirode
Mitsuhiro
M
Sagayama
Masumi
M
Maeda
Ryouta
R
Kawamoto
Makiko
M
Hirai
Kazuko
K
Terauchi
Jun
J
Sakura
Yasufumi
Y
Kakihana
Mitsuru
M
Kato
Kaneyoshi
K
Iwatsubo
Takeshi
T
Miyamoto
Masaomi
M
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D058255:Protease Nexins; D011897:Random Allocation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D016896:Treatment Outcome
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C551841:TAK-070; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse