Therapeutic potential of NADPH oxidase 1/4 inhibitors.
The NADPH oxidase (NOX) family of enzymes produces ROS as their sole function and is becoming recognized as key modulators of signal transduction pathways with a physiological role under acute stress and a pathological role after excessive activation under chronic stress. The seven isoforms differ in their regulation, tissue and subcellular localization and ROS products. The most studied are NOX1, 2 and 4. Genetic deletion of NOX1 and 4, in contrast to NOX2, has revealed no significant spontaneous pathologies and a pathogenic relevance of both NOX1 and 4 across multiple organs in a wide range of diseases and in particular inflammatory and fibrotic diseases. This has stimulated interest in NOX inhibitors for therapeutic application. GKT136901 and GKT137831 are two structurally related compounds demonstrating a preferential inhibition of NOX1 and 4 that have suitable properties for in vivo studies and have consequently been evaluated across a range of disease models and compared with gene deletion. In contrast to gene deletion, these inhibitors do not completely suppress ROS production, maintaining some basal level of ROS. Despite this and consistent with most gene deletion studies, these inhibitors are well tolerated and slow or prevent disease progression in a range of models of chronic inflammatory and fibrotic diseases by modulating common signal transduction pathways. Clinical trials in patients with GKT137831 have demonstrated excellent tolerability and reduction of various markers of chronic inflammation. NOX1/4 inhibition may provide a safe and effective therapeutic strategy for a range of inflammatory and fibrotic diseases.



This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
Evotec International GmbH, Goettingen, Germany.
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Teixeira
Genkyotex SA, Plan les Ouates, Switzerland.
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Szyndralewiez
Genkyotex SA, Plan les Ouates, Switzerland.
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Molango
Genkyotex SA, Plan les Ouates, Switzerland.
S
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Carnesecchi
Genkyotex SA, Plan les Ouates, Switzerland.
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F
Heitz
Genkyotex SA, Plan les Ouates, Switzerland.
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Wiesel
Inovaid, Biel-Benken, Switzerland.
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Wood
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D000074624:NADPH Oxidase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074662:NADPH Oxidase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D047069:Pyrazolones; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*
C554850:2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; D011728:Pyridones; C576694:setanaxib; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2