Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach

Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-12, Vol.21 (24), p.7277-7280
Main Authors: Xin, Zhili, Peng, Hairuo, Zhang, Andrew, Talreja, Tina, Kumaravel, Gnanasambandam, Xu, Lin, Rohde, Ellen, Jung, Mi-yong, Shackett, Melanie N., Kocisko, David, Chollate, Sowmya, Dunah, Anthone W., Snodgrass-Belt, Pamela A., Moore Arnold, H., Taveras, Arthur G., Rhodes, Kenneth J., Scannevin, Robert H.
Format: Article
Language:English
Subjects:
Administration, Oral
Alzheimer’s disease
Amyloid
Amyloid beta-Peptides - metabolism
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics
Biological and medical sciences
brain
Brain - metabolism
chemistry
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Medical sciences
Mice
Modulator
Neuropharmacology
nonsteroidal anti-inflammatory agents
oral administration
Peptide Fragments - metabolism
Pharmacology. Drug treatments
Phenylacetates - chemical synthesis
Phenylacetates - chemistry
Phenylacetates - pharmacokinetics
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacokinetics
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Rats
Scaffold design
γ-Secretase
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Description
Summary:Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.10.047