Piperazine Sulfonamide BACE1 Inhibitors: Design, Synthesis, and in Vivo Characterization

Bioorg Med Chem Lett. 2010 May 1;20(9):2837-42. doi: 10.1016/j.bmcl.2010.03.050. Epub 2010 Mar 12.

Abstract

With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2' sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Abeta(40) in transgenic mice with a single subcutaneous dose.

Publication types

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

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Piperazine
  • Piperazines / chemistry*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / therapeutic use
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / therapeutic use

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Piperazines
  • Protease Inhibitors
  • Sulfonamides
  • amyloid beta-protein (1-40)
  • Piperazine
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse

Associated data

  • PDB/3LNK
  • PDB/3LPI
  • PDB/3LPJ
  • PDB/3LPK