Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7255-60. doi: 10.1016/j.bmcl.2011.10.050. Epub 2011 Oct 20.

Abstract

Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Binding Sites
  • Computer Simulation
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Protein Structure, Tertiary
  • Stereoisomerism

Substances

  • Enzyme Inhibitors
  • Piperazines
  • Amyloid Precursor Protein Secretases