2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead

J Med Chem. 2007 Sep 6;50(18):4261-4. doi: 10.1021/jm0705408. Epub 2007 Aug 8.

Abstract

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / blood
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • CHO Cells
  • Caco-2 Cells
  • Cell Membrane Permeability
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Models, Molecular*
  • Molecular Conformation
  • Mutation
  • Oligopeptides / chemistry
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / blood
  • Peptide Fragments / metabolism
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • OM99-2
  • Oligopeptides
  • Peptide Fragments
  • Quinazolines
  • amyloid beta-protein (1-40)
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human