Thiophene substituted acylguanidines as BACE1 inhibitors

Bioorg Med Chem Lett. 2007 Oct 1;17(19):5353-6. doi: 10.1016/j.bmcl.2007.08.010. Epub 2007 Aug 11.

Abstract

A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Guanidines / chemical synthesis*
  • Guanidines / pharmacology*
  • Indicators and Reagents
  • Models, Molecular
  • Pyrroles / chemistry
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacology*

Substances

  • Enzyme Inhibitors
  • Guanidines
  • Indicators and Reagents
  • Pyrroles
  • Thiophenes
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human