Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase

J Med Chem. 2007 Feb 22;50(4):776-81. doi: 10.1021/jm061242y.

Abstract

The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid beta-Protein Precursor / chemistry
  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Models, Molecular*
  • Molecular Mimicry
  • Molecular Structure
  • Peptides / chemistry*
  • Phthalic Acids / chemical synthesis*
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology
  • Stereoisomerism

Substances

  • Amyloid beta-Protein Precursor
  • N-(1-(3,5-difluorobenzyl)-2-hydroxy-3-(3-iodobenzylamino)propyl)-5-methyl-N',N'-dipropylisophthalamide
  • Peptides
  • Phthalic Acids
  • Amyloid Precursor Protein Secretases