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. Epub 2011 Oct 19.

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.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Brain / metabolism
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Mice
  • Peptide Fragments / metabolism
  • Phenylacetates / chemical synthesis
  • Phenylacetates / chemistry*
  • Phenylacetates / pharmacokinetics
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Rats

Substances

  • Amyloid beta-Peptides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Peptide Fragments
  • Phenylacetates
  • Piperidines
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases
  • phenylacetic acid