Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits

Bioorg Med Chem Lett. 2007 Jan 15;17(2):414-8. doi: 10.1016/j.bmcl.2006.10.028. Epub 2006 Oct 17.

Abstract

We report the development of a novel, aqueous-soluble, safe, small molecule, experimental therapeutic that suppresses injury-induced, proinflammatory cytokine increases in the brain, with resultant attenuation of synaptic protein biomarker loss and improvement in hippocampus-dependent behavioral deficits. A GMP production scheme for the active pharmaceutical ingredient, compound 17, is presented. The development and large-scale availability of this novel compound allow exploration of new, potentially disease-modifying, therapeutic approaches to CNS disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / drug therapy
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Behavior, Animal / drug effects*
  • Biological Availability
  • Brain Chemistry / drug effects*
  • Chemical Phenomena
  • Chemistry, Physical
  • Cytokines / biosynthesis*
  • Drug Design
  • Glial Fibrillary Acidic Protein / biosynthesis
  • Hippocampus / drug effects
  • Magnetic Resonance Spectroscopy
  • Mice
  • Microglia / drug effects
  • Nootropic Agents / chemical synthesis*
  • Nootropic Agents / pharmacology*
  • Nootropic Agents / toxicity
  • Pyridazines / chemical synthesis*
  • Pyridazines / pharmacology*
  • Pyridazines / toxicity
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Pyrimidines / toxicity
  • Rats
  • Synapses / drug effects*
  • Synapses / metabolism
  • Up-Regulation / drug effects

Substances

  • Cytokines
  • Glial Fibrillary Acidic Protein
  • Nootropic Agents
  • Pyridazines
  • Pyrimidines
  • minozac