Pyridinyl aminohydantoins as small molecule BACE1 inhibitors

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2326-9. doi: 10.1016/j.bmcl.2010.01.136. Epub 2010 Feb 12.

Abstract

A novel class of pyridinyl aminohydantoins was designed and prepared as highly potent BACE1 inhibitors. Compound (S)-4g showed excellent potency with IC(50) of 20 nM for BACE1. X-ray crystallography indicated that the interaction between pyridine nitrogen and the tryptophan Trp76 was a key feature in the S2' region of the enzyme that contributed to increased potency.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / metabolism*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Hydantoins / chemistry
  • Hydantoins / pharmacology*
  • Models, Molecular
  • Protein Binding
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Hydantoins
  • Pyridines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human