Small-molecule NOX inhibitors: ROS-generating NADPH oxidases as therapeutic targets.
NOX NADPH oxidases are electron-transporting membrane enzymes whose primary function is the generation of reactive oxygen species (ROS). ROS produced by NOX enzymes show a variety of biologic functions, such as microbial killing, blood pressure regulation, and otoconia formation. Strong evidence suggests that NOX enzymes are major contributors to oxidative damage in pathologic conditions. Blocking the undesirable actions of NOX enzymes, therefore, is a therapeutic strategy for treating oxidative stress-related pathologies, such as ischemia/reperfusion tissue injury, and neurodegenerative and metabolic diseases. Most currently available NOX inhibitors have low selectivity, potency, and bioavailability, precluding a pharmacologic demonstration of NOX as therapeutic targets in vivo. This review has two main purposes. First, we describe a systematic approach that we believe should be followed in the search for truly selective NOX inhibitors. Second, we present a critical review of small-molecule NOX inhibitors described over the last two decades, including recently published patents from the pharmaceutical industry. Structures, activities, and in vitro/in vivo specificity of these NOX inhibitors are discussed. We conclude that NOX inhibition is a pertinent and promising novel pharmacologic concept, but that major efforts will be necessary to develop specific NOX inhibitors suited for clinical application.
Jaquet
Vincent
V
Department of Pathology and Immunology, Centre Médical Universitaire, School of Pharmaceutical Sciences, University of Geneva, Switzerland. Vincent.Jaquet@unige.ch
Scapozza
Leonardo
L
Clark
Robert A
RA
Krause
Karl-Heinz
KH
Lambeth
J David
JD
D015195:Drug Design; D004345:Drug Industry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases