Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species

J Med Chem. 2013 Apr 25;56(8):3379-403. doi: 10.1021/jm4002154. Epub 2013 Apr 16.


A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Blood-Brain Barrier / metabolism
  • Chromans / chemical synthesis
  • Chromans / pharmacokinetics
  • Chromans / pharmacology
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • Hydantoins / chemical synthesis
  • Hydantoins / pharmacokinetics
  • Hydantoins / pharmacology
  • Male
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology
  • Rats
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship


  • Amyloid beta-Peptides
  • Chromans
  • Hydantoins
  • Protease Inhibitors
  • Spiro Compounds
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Associated data

  • PDB/4JOO
  • PDB/4JP9
  • PDB/4JPC
  • PDB/4JPE