Design and synthesis of BACE1 inhibitors containing a novel norstatine derivative (2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1629-33. doi: 10.1016/j.bmcl.2006.12.097. Epub 2007 Jan 8.

Abstract

A novel norstatine derivative, phenylthionorstatine [(2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid; Ptns], containing a hydroxymethylcarbonyl (HMC) isostere was designed, synthesized, and stereochemically determined. Then, Ptns was introduced into the structure of BACE1 inhibitors at the P(1) position. Finally, Ptns was found as a suitable P(1) moiety for potent BACE1 inhibitor design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminocaproates / chemistry*
  • Aminocaproates / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Butyrates / chemical synthesis*
  • Butyrates / pharmacology*
  • Chromatography, High Pressure Liquid
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indicators and Reagents
  • Molecular Conformation
  • Spectrometry, Mass, Fast Atom Bombardment
  • Structure-Activity Relationship

Substances

  • (2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid
  • Aminocaproates
  • Butyrates
  • Enzyme Inhibitors
  • Indicators and Reagents
  • 3-amino-2-hydroxy-5-methylhexanoic acid
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human