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Linda Jo Van Eldik1, Saktimayee M Roy2, Ottavio Arancio3

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Researchers developed novel small molecules to target brain inflammation in neurodegenerative diseases like Alzheimer's disease (AD). Three drug candidates are now in clinical trials, offering hope for new therapeutic strategies.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Drug Discovery

Background:

  • Dysregulated brain inflammation, particularly proinflammatory cytokine overproduction, is a key driver of neurodegenerative diseases such as Alzheimer's disease (AD).
  • This neuroinflammation is linked to activated glia and synaptic dysfunction, highlighting the need for therapeutic interventions.
  • Inefficient, excessive, or prolonged inflammatory responses in the central nervous system (CNS) can be detrimental to homeostasis.

Purpose of the Study:

  • To discover and develop novel pharmacological agents that can attenuate dysregulated proinflammatory cytokine production.
  • To restore glia-neuronal homeostasis by modulating key inflammatory pathways.
  • To identify therapeutic candidates targeting specific cytokine panels relevant to disease progression.

Main Methods:

  • Utilized unbiased phenotypic and single molecular target approaches for drug discovery.
  • Designed and synthesized small molecules based on the pyridazine chemotype, guided by pharmacoinformatics.
  • Employed recursive screening, medicinal chemistry, secondary pharmacology assays, and in vivo efficacy studies in animal models.

Main Results:

  • Developed a series of drug candidates exhibiting oral bioavailability and brain exposure.
  • Demonstrated promising safety profiles and efficacy at low doses in animal models of CNS disorders.
  • Advanced three therapeutic candidates (MW150, MW151, MW189) into human phase 1b/2a clinical trials.

Conclusions:

  • Emphasized the importance of focusing drug discovery on disease-relevant pathophysiology and strategic compound design.
  • Highlighted the need for interventions targeting complementary disease drivers and appropriate therapeutic windows for complex diseases like AD.
  • Validated the cytokine/synaptic dysfunction axis as a viable target for therapeutic intervention in neurodegenerative disease progression.