Abstract
Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aβ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.
MeSH terms
-
Alzheimer Disease / drug therapy
-
Alzheimer Disease / genetics
-
Alzheimer Disease / pathology*
-
Amyloid / metabolism*
-
Amyloid Precursor Protein Secretases / antagonists & inhibitors
-
Amyloid Precursor Protein Secretases / metabolism
-
Amyloid beta-Peptides / metabolism
-
Amyloid beta-Protein Precursor / genetics
-
Amyloid beta-Protein Precursor / metabolism
-
Animals
-
Aspartic Acid Endopeptidases / antagonists & inhibitors
-
Aspartic Acid Endopeptidases / metabolism
-
Cells, Cultured
-
Cerebral Cortex / pathology
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Embryo, Mammalian
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Enzyme Inhibitors / therapeutic use
-
Female
-
Guinea Pigs
-
Humans
-
Isoindoles / pharmacology
-
Isoindoles / therapeutic use
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Mutation / genetics
-
Neurons / drug effects*
-
Neurons / metabolism*
-
Peptide Fragments / metabolism
-
Pyridones / pharmacology
-
Pyridones / therapeutic use
-
Time Factors
Substances
-
AZ-4217
-
Amyloid
-
Amyloid beta-Peptides
-
Amyloid beta-Protein Precursor
-
Enzyme Inhibitors
-
Isoindoles
-
Peptide Fragments
-
Pyridones
-
amyloid beta-protein (1-40)
-
amyloid beta-protein (1-42)
-
Amyloid Precursor Protein Secretases
-
Aspartic Acid Endopeptidases
-
BACE1 protein, human