2. Academic Validation
  3. Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach

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

  • Bioorg Med Chem Lett. 2011 Dec 15;21(24):7277-80. doi: 10.1016/j.bmcl.2011.10.047.
Zhili Xin 1,  Hairuo Peng,  Andrew Zhang,  Tina Talreja,  Gnanasambandam Kumaravel,  Lin Xu,  Ellen Rohde,  Mi-yong Jung,  Melanie N Shackett,  David Kocisko,  Sowmya Chollate,  Anthone W Dunah,  Pamela A Snodgrass-Belt,  H Moore Arnold,  Arthur G Taveras,  Kenneth J Rhodes,  Robert H Scannevin
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. zhili.xin@biogenidec.com
PMID: 22061640 DOI: 10.1016/j.bmcl.2011.10.047
Abstract

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.

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