Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors

Bioorg Med Chem Lett. 2013 May 15;23(10):3075-80. doi: 10.1016/j.bmcl.2013.03.009. Epub 2013 Mar 21.

Abstract

Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • G 1617
  • Isoquinolines
  • Protease Inhibitors
  • Thiophenes
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human