Structure based design of iminohydantoin BACE1 inhibitors: identification of an orally available, centrally active BACE1 inhibitor

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2444-9. doi: 10.1016/j.bmcl.2012.02.013. Epub 2012 Feb 16.

Abstract

From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / blood
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / blood
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / pharmacology
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydantoins / chemical synthesis*
  • Hydantoins / pharmacology
  • Models, Molecular
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Amyloid beta-Peptides
  • Anticonvulsants
  • Enzyme Inhibitors
  • Hydantoins
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, rat