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The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans
- Publication Year :
- 2015
- Publisher :
- Society for Neuroscience, 2015.
-
Abstract
- BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translatesin vitroactivity into robustin vivoamyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
- Subjects :
- Proteases
Amyloid
Amyloid beta
medicine.medical_treatment
Pharmacology
Heterocyclic Compounds, 2-Ring
Pathogenesis
Mice
Dogs
In vivo
Alzheimer Disease
mental disorders
medicine
Animals
Aspartic Acid Endopeptidases
Humans
Protease Inhibitors
Picolinic Acids
Protease
Amyloid beta-Peptides
biology
Drug discovery
General Neuroscience
Articles
In vitro
Disease Models, Animal
biology.protein
Amyloid Precursor Protein Secretases
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....f78c69adc5fae76e66024d7197aeccfc