Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads

Bioorg Med Chem Lett. 2010 May 15;20(10):3158-60. doi: 10.1016/j.bmcl.2010.03.097. Epub 2010 Mar 30.

Abstract

We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Computer Simulation
  • Humans
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry*
  • Macrocyclic Compounds / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • Structure-Activity Relationship

Substances

  • Macrocyclic Compounds
  • Protease Inhibitors
  • Quinazolines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human