NADPH oxidase inhibitors: a patent review

Abstract

Since each member of the NADPH oxidase family has great potential as a therapeutic target, several different compounds have been registered as NADPH oxidase inhibitors in the patent literature. As yet, none have gone through clinical trials, and some have not completed preclinical trials, including safety and specificity evaluation. Recently, small molecule pyrazolopyridine and triazolopyrimidine derivatives have been submitted as potent NADPH oxidase inhibitors and reported as first-in-class inhibitors for idiopathic pulmonary fibrosis and acute stroke, respectively. Further clinical efficacy and safety data are warranted to prove their actual clinical utility.

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…Of the many enzymes that are potential therapeutic targets are Noxs. Due to this, there has been enormous interest in the development of agents that inhibit Noxs in an isoform-specific manner (91,102,194,197). Different strategies have been employed, including smallmolecule inhibitors, peptide Nox inhibitors, and siRNAS.…”

“…Different strategies have been employed, including smallmolecule inhibitors, peptide Nox inhibitors, and siRNAS. Several pharmacological compounds have been registered as Nox inhibitors in the patent literature (102). First-generation Nox inhibitors, including apocynin and diphenylene iodinium, are non specific, lack selectivity, and have multiple ''offtarget'' side effects.…”

“…Newer-generation NOX inhibitors are more specific and selective. To date, two different classes of compounds have been claimed as potent selective and orally active bioavailable Nox inhibitors: pyrazolopyridines (GKT136901 and GKT137831) and triazolopyrimidine derivatives (VAS2870 and VAS3947) (39,91,102,194,197). These agents target mainly Nox1 and Nox4, and, apparently, have a few ''off-target'' side effects (22, 217).…”

Oxidative Stress in Human Health and Disease

“…To date six human isoforms have been isolated (Nox 1, 3, 4, 5, and Duox 1 and 2) (19,20). They utilize a system that is dependent on NADPH, although, NADH can also be used as substrate (21). As a result they are referred to as NAD(P)H oxidases (12,22).…”

Oxidative Stress and Novel Antioxidant Approaches to Reduce Diabetic Complications

“…Several small molecule and peptide inhibitors of the NOX enzymes have been developed and are showing promise in experimental studies, but issues of specificity, potency and toxicity militate against any of the existing compounds as candidates for drug development (Kim et al 2011;Williams & Griendling 2007). In a recent study, apocynin, a proven NADPH oxidase inhibitor, attenuated albuminuria, improved kidney structure (glomerular and mesangial expansion) and reduced oxidative stress (urinary 8-OHdG and malondialdehyde) in aged Otsuka Long Evans Tokushima Fatty (OLETF) rats (Nam et al 2009).…”