Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2477-80. doi: 10.1016/j.bmcl.2014.04.012. Epub 2014 Apr 13.

Abstract

The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110 nM) demonstrated a reduction in CSF Aβ in wild type rats after a single dose.

Keywords: Alzheimer’s disease; BACE1 inhibitors; Structure-based ligand design.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Benzopyrans / chemical synthesis
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Microsomes, Liver / enzymology
  • Molecular Conformation
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Swine

Substances

  • 7'-(5-chloropyridin-3-yl)-3',4',4a',10a'-tetrahydro-1'H,5H-spiro(oxazole-4,5'-pyrano(3,4-b)chromen)-2-amine
  • Amyloid beta-Peptides
  • Benzopyrans
  • Oxazoles
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human