Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors

Bioorg Med Chem Lett. 2007 Jul 15;17(14):4057-61. doi: 10.1016/j.bmcl.2007.04.072. Epub 2007 Apr 27.

Abstract

This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry*
  • Amines / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cyclization
  • Drug Design
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amines
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human