Validation of the neuroinflammation cycle as a drug discovery target using integrative chemical biology and lead compound development with an Alzheimer's disease-related mouse model

Wenhui Hu, Hantamalala Ralay Ranaivo, Jeffrey M. Craft, Linda J. Van Eldik, D. Martin Watterson*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The neuroinflammation cycle has been proposed as a potential therapeutic target in the development of new approaches to altering Alzheimer's disease (AD) progression. However, the efficacy and toxicological profile of compounds that focus only on classical NSAID targets have been disappointing to date. Therefore, we recently initiated an unbiased, integrative chemical biology approach that used a hierarchal set of cell-based screens, followed by efficacy analysis in a new AD-relevant animal model that more closely resembles human pathology endpoints in terms of neuroinflammation and neuronal loss. The prior investigations provided a proof of concept that targeting the neuroinflammation cycle may be a viable drug discovery approach for AD. However, recent informatics analyses of the high attrition rate in drug development have identified the need for starting drug development with lead compounds that are well below cut off values in computed molecular properties in order to facilitate late stage medicinal chemistry refinement to improve in vivo functions. We describe here how we are leveraging our novel, unbiased, integrative chemical biology approach for the rapid discovery of potential lead compounds for AD drug discovery. Specifically, we show that orally bioavailable compounds with the desired physical properties and in vivo functions can be identified in focused synthetic libraries composed of chemical diversifications of the inactive but privileged pyridazine molecular fragment.

Original languageEnglish (US)
Pages (from-to)197-205
Number of pages9
JournalCurrent Alzheimer Research
Volume2
Issue number2
DOIs
StatePublished - Apr 1 2005

Keywords

  • Alzheimer's disease
  • Animal model
  • Cytokines
  • Drug discovery
  • Glia
  • Neuroinflammation
  • Pyridazines

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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