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 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.
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,Taveras, Arthur G.,Rhodes, Kenneth J.,Scannevin, Robert H.
p. 7277 - 7280
(2012/02/04)
CARBOXYLIC ACID-CONTAINING COMPOUNDS, DERIVATIVES THEREOF, AND RELATED METHODS OF USE
Compounds that modulate gamma secretase (e.g., alter the cleavage pattern of gamma secretase) are described herein. Also disclosed are pharmaceutical compositions, methods of modulating the activity of gamma secretase, and methods of treating Alzheimer's Disease using the compounds described herein.
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Page/Page column 108-109
(2010/12/26)
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