title: Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor.
abstract: OBJECTIVE
  The NADPH oxidase (NOX) family of enzymes catalyzes the formation of reactive oxygen species (ROS). NOX enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. To date, while numerous small molecule inhibitors have been reported (in particular for NOX2), none have demonstrated inhibitory activity in vivo. As such, there is a need for the identification of improved NOX inhibitors to enable further evaluation of the biological functions of NOX enzymes in vivo as well as the therapeutic potential of NOX inhibition. In this study, both the in vitro and in vivo pharmacological profiles of GSK2795039, a novel NOX2 inhibitor, were characterized in comparison with other published NOX inhibitors.
  
  
  RESULTS
  GSK2795039 inhibited both the formation of ROS and the utilization of the enzyme substrates, NADPH and oxygen, in a variety of semirecombinant cell-free and cell-based NOX2 assays. It inhibited NOX2 in an NADPH competitive manner and was selective over other NOX isoforms, xanthine oxidase, and endothelial nitric oxide synthase enzymes. Following systemic administration in mice, GSK2795039 abolished the production of ROS by activated NOX2 enzyme in a paw inflammation model. Furthermore, GSK2795039 showed activity in a murine model of acute pancreatitis, reducing the levels of serum amylase triggered by systemic injection of cerulein.
  
  
  CONCLUSIONS
  GSK2795039 is a novel NOX2 inhibitor that is the first small molecule to demonstrate inhibition of the NOX2 enzyme in vivo.
authors.affiliation: 1 Neural Pathways Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Biopolis, Singapore .
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authors.affiliation: 1 Neural Pathways Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Biopolis, Singapore .
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authors.affiliation: 1 Neural Pathways Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Biopolis, Singapore .
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authors.affiliation: 1 Neural Pathways Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Biopolis, Singapore .
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authors.forename: Dizheng
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authors.lastname: Li
authors.affiliation: 5 Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline , King of Prussia, Pennsylvania.
authors.forename: Douglas G
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authors.affiliation: 1 Neural Pathways Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Biopolis, Singapore .
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authors.affiliation: 1 Neural Pathways Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Biopolis, Singapore .
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authors.affiliation: 2 Department of Pathology and Immunology, Medical School, Centre Médical Universitaire, University of Geneva , Geneva, Switzerland .
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mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010195:Pancreatitis / Q000188:drug therapy; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; C000607558:GSK2795039; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases