Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors

Cifuentes-Pagano, Eugenia; Saha, Jaideep; Csányi, Gábor; Ghouleh, Imad Al; Sahoo, Sanghamitra; Rodríguez, Andrés; Wipf, Peter; Pagano, Patrick J.; Skoda, Erin M.

doi:10.1039/c3md00061c

Cited by 31 publications

(29 citation statements)

References 59 publications

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“…The authors further noted that the anti-ROS therapy decreased cerebral amyloid angiopathy and micro-hemorrhage that commonly occur in Alzheimer’s Disease [188]. As all these studies point to the key contribution of the Nox, particularly Nox2, to aging-elicited cerebrovascular dysfunction, Nox2 inhibition holds great promise as a therapeutic strategy [52,189–191] for restoring vascular health in cerebral microcirculation, and hopefully delaying the onset of cognitive impairment.…”

Section: Cerebral Microcirculationmentioning

confidence: 99%

“…Using high throughput screening and rational design, our laboratory identified bridged tetrahydroquinolines as specific Nox2 inhibitors [191]. Among a group of structurally related molecules, compounds 11 g [(±)-(1S,4R,9S)-5-bromo-3,3-dimethyl-9-(2-methylallyl)−10-pentyl-1,2,3,4-tetrahydro-1,3-(epiminomehono) naphthalene] and 11 h [(±)-(1S,4R,9S)-5-bromo-3,3-dimethyl-9-(2-methyallyl)-10-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydro-1,4-(epino-methano)naphthalene] displayed isoform-selective inhibition on Nox2 in intact COS-Nox2 cells with IC 50 of 20 μM and 32 μM, respectively.…”

Section: Nox Inhibitors As Therapeutics For Microvascular Diseasesmentioning

confidence: 99%

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Microvascular NADPH oxidase in health and disease

Pagano

2017

Free Radical Biology and Medicine

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The systemic and cerebral microcirculation contribute critically to regulation of local and global blood flow and perfusion pressure. Microvascular dysfunction, commonly seen in numerous cardiovascular pathologies, is associated with alterations in the oxidative environment including potentiated production of reactive oxygen species (ROS) and subsequent activation of redox signaling pathways. NADPH oxidases (Noxs) are a primary source of ROS in the vascular system and play a central role in cardiovascular health and disease. In this review, we focus on the roles of Noxs in ROS generation in resistance arterioles and capillaries, and summarize their contributions to microvascular physiology and pathophysiology in both systemic and cerebral microcirculation. In light of the accumulating evidence that Noxs are pivotal players in vascular dysfunction of resistance arterioles, selectively targeting Nox isozymes could emerge as a novel and effective therapeutic strategy for preventing and treating microvascular diseases.

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Section: Cerebral Microcirculationmentioning

confidence: 99%

Section: Nox Inhibitors As Therapeutics For Microvascular Diseasesmentioning

confidence: 99%

Microvascular NADPH oxidase in health and disease

Pagano

2017

Free Radical Biology and Medicine

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“…Like the first-generation GKT inhibitor, issues of Nox specificity are still a concern with regard to untoward and off-target effects of these drugs. Novel approaches and rational drug design strategies have yielded isoform selectivity for Nox2 and been discussed in greater detail [107,108,247,258,266]. Assuredly with these innovative approaches, new isoform-specific Nox therapeutics are expected to gain greater traction.…”

Section: Nox In Age-associated Cvdmentioning

confidence: 99%

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

2016

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Reactive oxygen species (ROS) and oxidative stress have long been linked to aging and diseases prominent in the elderly such as hypertension, atherosclerosis, diabetes and atrial fibrillation (AF). NADPH oxidases (Nox) are a major source of ROS in the vasculature and are key players in mediating redox signalling under physiological and pathophysiological conditions. In this review, we focus on the Nox-mediated ROS signalling pathways involved in the regulation of ‘longevity genes’ and recapitulate their role in age-associated vascular changes and in the development of age-related cardiovascular diseases (CVDs). This review is predicated on burgeoning knowledge that Nox-derived ROS propagate tightly regulated yet varied signalling pathways, which, at the cellular level, may lead to diminished repair, the aging process and predisposition to CVDs. In addition, we briefly describe emerging Nox therapies and their potential in improving the health of the elderly population.

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“…Despite decades of research, only a limited number of Nox inhibitors are currently available, few if any of which are isoform-specific; researchers are therefore actively seeking new small molecules as isoform-selective Nox inhibitors (17)(18)(19)(20). The limited progress thus far is due in part to limitations of the assays that are currently in use for detection and quantitation of ROS (21).…”

mentioning

confidence: 99%

High-throughput Assays for Superoxide and Hydrogen Peroxide

Zielonka¹,

Cheng²,

Zielonka³

et al. 2014

Journal of Biological Chemistry

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Background: NADPH oxidases (Nox) are involved in pathogenesis of inflammatory and fibrotic diseases. Results: High-throughput screening methodology is developed for discovery and determination of Nox inhibitors and mechanism. Conclusion: Rapid and specific monitoring of superoxide and hydrogen peroxide is possible, enabling high-throughput screening of Nox isoform-specific inhibitors. Significance: The proposed strategy will enable more rigorous research on the chemical biology of Nox enzymes.

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Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors

Cited by 31 publications

References 59 publications

Microvascular NADPH oxidase in health and disease

Microvascular NADPH oxidase in health and disease

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

High-throughput Assays for Superoxide and Hydrogen Peroxide

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