Design, Synthesis, and Evaluation of a Novel Series of Oxadiazine Gamma Secretase Modulators for Familial Alzheimer's Disease

J Med Chem. 2017 Mar 23;60(6):2383-2400. doi: 10.1021/acs.jmedchem.6b01620. Epub 2017 Mar 10.

Abstract

Herein we describe the design, synthesis, and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aβ42 reductions and subsequent Aβ37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line
  • Drug Design*
  • Humans
  • Macaca fascicularis
  • Mice
  • Oxazines / chemistry*
  • Oxazines / pharmacokinetics
  • Oxazines / pharmacology*
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Rats, Wistar

Substances

  • Amyloid beta-Peptides
  • Oxazines
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases