Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators

Bioorg Med Chem. 2020 Nov 15;28(22):115734. doi: 10.1016/j.bmc.2020.115734. Epub 2020 Sep 1.

Abstract

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aβ42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aβ42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aβ42 levels in the plasma of J20 mice, in addition to reducing Aβ42 levels in the plasma and brain of Tg2576 mice.

Keywords: Alzheimer’s disease; Amyloid beta; Aβ42 reduction; Gamma secretase modulator; Methoxypyridines; Structure activity relationship.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / analysis
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / biosynthesis
  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Pyridines
  • Amyloid Precursor Protein Secretases