Discovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations

J Med Chem. 2005 Aug 11;48(16):5108-11. doi: 10.1021/jm050499d.

Abstract

A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM were measured in at least one of two different mammalian cell-based assays for 12 of the 72 purchased compounds. In particular, the phenylureathiadiazole 2 and the diphenylurea derivative 3 are promising lead compounds for beta-secretase inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry*
  • Binding Sites
  • Carbanilides / chemical synthesis*
  • Carbanilides / chemistry
  • Carbanilides / pharmacology
  • Cell Line
  • Cell Membrane Permeability
  • Databases, Factual
  • Endopeptidases
  • Fluorescence Resonance Energy Transfer
  • Mammals
  • Models, Molecular
  • Phenylurea Compounds / chemical synthesis*
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology
  • Static Electricity
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis*
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology

Substances

  • Carbanilides
  • Phenylurea Compounds
  • Thiadiazoles
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases