Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3β inhibitors

Angew Chem Int Ed Engl. 2015 Jan 26;54(5):1578-82. doi: 10.1002/anie.201410456. Epub 2014 Dec 11.

Abstract

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3β. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) μM and (14.67±0.78) μM for BACE-1 and GSK-3β, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.

Keywords: drug design; drug discovery; enzymes; heterocycles; neurochemistry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Blood-Brain Barrier / metabolism
  • Catalytic Domain
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacokinetics
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Half-Life
  • Lipopolysaccharides / toxicity
  • Mice
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / metabolism
  • Molecular Docking Simulation
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Binding
  • Rats
  • Triazines / chemistry*
  • Triazines / metabolism
  • Triazines / pharmacology
  • Up-Regulation / drug effects

Substances

  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Triazines
  • Nitric Oxide Synthase Type II
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse