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NOX2 inhibitor GSK2795039 metabolite identification towards drug optimization

Elias Carvalho Padilha1, Pranav Shah1, Ganesha Rai1

  • 1Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, United States.

Journal of Pharmaceutical and Biomedical Analysis
|May 16, 2021
PubMed

Insights

This study identified metabolic "soft spots" in the NOX2 inhibitor GSK2795039, revealing species-specific metabolism crucial for optimizing drug properties and improving preclinical safety evaluations.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Medicinal Chemistry

Background:

  • Reactive oxygen species (ROS) contribute to diseases like diabetic nephropathy.
  • NADPH oxidase (NOX) enzymes are key targets for inhibiting ROS production.
  • GSK2795039 selectively inhibits NOX2 but exhibits high clearance in preclinical species.

Purpose of the Study:

  • To identify metabolic soft spots in GSK2795039 to guide pharmacokinetic optimization.
  • To understand species-specific metabolism of GSK2795039 in mouse, rat, and human liver fractions.
  • To inform structure-activity relationship studies for developing improved NOX2 inhibitors.

Main Methods:

  • Incubation of GSK2795039 with mouse, rat, and human liver microsomes and cytosol.
  • Utilized MS^e fragment analysis to identify metabolic soft spots.
  • Characterized GSK2795039 as an aldehyde oxidase substrate.

Main Results:

  • Significant species differences in GSK2795039 metabolism were observed.
  • Alkyl side chains and the indoline moiety were primary sites of biotransformation.
  • Unique human metabolites were identified in vitro, and aldehyde oxidase activity was confirmed.

Conclusions:

  • Metabolic profiling provides critical insights for optimizing GSK2795039's pharmacokinetic properties.
  • Understanding species-specific metabolism aids in selecting appropriate preclinical models for safety assessment.
  • This research facilitates the development of more effective NOX2 inhibitors with improved drug-like properties.
Keywords:
Aldehyde oxidase metabolismGSK2795039Metabolite identificationNOX2 inhibitorStructure optimization

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