The quest for selective nox inhibitors and therapeutics: challenges, triumphs and pitfalls.
CONCLUSIONS
Numerous studies in animal models and human subjects corroborate that elevated levels of reactive oxygen species (ROS) play a pivotal role in the progression of multiple diseases. As a major source of ROS in many organ systems, the NADPH oxidase (Nox) has become a prime target for therapeutic development.


BACKGROUND
In recent years, intense efforts have been dedicated to the development of pan- and isoform-specific Nox inhibitors as opposed to antioxidants that proved ineffective in clinical trials. Over the past decade, an array of compounds has been proposed in an attempt to fill this void.


RESULTS
Although many of these compounds have proven effective as Nox enzyme family inhibitors, isoform specificity has posed a formidable challenge to the scientific community. This review surveys the most prominent Nox inhibitors, and discusses potential isoform specificity, known mechanisms of action, and shortcomings. Some of these inhibitors hold substantial promise as targeted therapeutics.


CONCLUSIONS
Increased insight into the mechanisms of action and regulation of this family of enzymes as well as atomic structures of key Nox subunits are expected to give way to a broader spectrum of more potent, efficacious, and specific molecules. These lead molecules will assuredly serve as a basis for drug development aimed at treating a wide array of diseases associated with increased Nox activity.
Department of Pharmacology and Chemical Biology, Vascular Medicine Institute, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
Eugenia
E
Cifuentes-Pagano
Daniel N
DN
Meijles
Patrick J
PJ
Pagano
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases