Rational design and synthesis of potent dibenzazepine motifs as beta-secretase inhibitors

J Med Chem. 2009 Oct 22;52(20):6484-8. doi: 10.1021/jm9008482.

Abstract

We have identified small-molecule dibenzazepine inhibitors of beta-secretase (BACE1). These BACE1 inhibitors possess two key salient features. The first is a seven-membered heterocyclic ring fused to two aromatic rings representing the P3-P2 residues. The second is an amide and/or amide bioisostere representing the P1' residue. Rational optimization led to the identification of potent analogues, such as 10 (K(I) = 211 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Dibenzazepines / chemical synthesis*
  • Dibenzazepines / chemistry
  • Dibenzazepines / pharmacology*
  • Drug Design*
  • Imidazoles / chemistry
  • Inhibitory Concentration 50
  • Phthalic Acids / chemistry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amides
  • Dibenzazepines
  • Imidazoles
  • Phthalic Acids
  • Protease Inhibitors
  • isophthalate
  • imidazole
  • Amyloid Precursor Protein Secretases
  • dibenzazepine