Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2195-2200. doi: 10.1016/j.bmcl.2018.05.003. Epub 2018 May 3.

Abstract

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen.

Keywords: Alzheimer’s disease; Amino-1,4-oxazines; BACE-1; P-gp; pK(a).

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Madin Darby Canine Kidney Cells / drug effects
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Oxazines / chemical synthesis
  • Oxazines / chemistry
  • Oxazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Oxazines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse