Discovery and initial optimization of 5,5'-disubstituted aminohydantoins as potent beta-secretase (BACE1) inhibitors

Bioorg Med Chem Lett. 2010 Jan 15;20(2):632-5. doi: 10.1016/j.bmcl.2009.11.052. Epub 2009 Nov 20.

Abstract

8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydantoins / chemical synthesis
  • Hydantoins / chemistry*
  • Hydantoins / pharmacology
  • Hydrogen Bonding
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology

Substances

  • Enzyme Inhibitors
  • Hydantoins
  • Imidazoles
  • Amyloid Precursor Protein Secretases