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
  • 1. Department of Medicinal Chemistry, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. [email protected]
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.