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Pharmacology of JNJ-28583113: A novel TRPM2 antagonist

Lawrence Fourgeaud1, Curt Dvorak1, Malika Faouzi2

  • 1Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA.

European Journal of Pharmacology
|April 10, 2019
PubMed

Insights

Researchers discovered JNJ-28583113, a potent TRPM2 antagonist that penetrates the brain. While effective in vitro for CNS disorders, its rapid metabolism requires optimization for in vivo use.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Transient receptor potential melastatin type 2 (TRPM2) channels are implicated in central nervous system (CNS) disorders.
  • TRPM2 is activated by intracellular ADP-ribose and reactive oxygen species, contributing to neuropathic pain, bipolar disorder, and Alzheimer's disease.

Purpose of the Study:

  • To discover and characterize JNJ-28583113, a novel, brain-penetrant TRPM2 antagonist.
  • To evaluate the in vitro and in vivo properties of JNJ-28583113 for potential therapeutic applications in CNS disorders.

Main Methods:

  • Utilized Ca2+ flux assays and electrophysiological recordings to assess TRPM2 antagonist activity.
  • Performed in vitro assays measuring GSK-3 phosphorylation, cell death, cytokine release in microglia, and morphological changes.
  • Evaluated pharmacokinetic properties of JNJ-28583113 in animal models.

Main Results:

  • JNJ-28583113 demonstrated potent TRPM2 antagonism (126 ± 0.5 nM).
  • TRPM2 inhibition by JNJ-28583113 affected GSK3 phosphorylation, protected cells from oxidative stress, and reduced microglial cytokine release.
  • JNJ-28583113 exhibited brain penetrance but rapid in vivo metabolism, limiting systemic dosing suitability.

Conclusions:

  • JNJ-28583113 possesses best-in-class in vitro TRPM2 antagonist properties.
  • Further optimization of in vivo pharmacokinetics is necessary for JNJ-28583113 to effectively target TRPM2 in CNS pathophysiology.
Keywords:
Cell deathCytokineMicrogliaOxidative stressTRPM2 antagonist

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