A Novel Small Molecule Modulator of Amyloid Pathology

Mark A. Lovell, Bert C. Lynn, Shuling Fister, Melissa Bradley-Whitman, M. Paul Murphy, Tina L. Beckett, Christopher M. Norris

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.

Original languageEnglish
Article numberJAD151160
Pages (from-to)273-287
Number of pages15
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - Jun 22 2016


  • Amyloid-β protein precursor
  • Elk-1
  • presenilin-1
  • presenilin-2

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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