Structure–activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: Carboxamide modification

Sun, Xicheng; Qiu, Jian; Strong, Sarah A.; Green, Louis S.; Wasley, Jan W. F.; Blonder, Joan P.; Colagiovanni, Dorothy B.; Stout, Adam M.; Mutka, Sarah C.; Richards, Jane P.; Rosenthal, Gary J.

doi:10.1016/j.bmcl.2012.01.047

Cited by 16 publications

(15 citation statements)

References 25 publications

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“…Importantly, reduction in IL-13 levels using IL-13 deficient mice or IL-13 neutralization strategies have confirmed an essential role for this cytokine in driving major correlates of asthma pathology, including AHR, pulmonary eosinophilia, and mucus secretion [28], [29]. Recently, Sun et al [30] have also identified a novel GSNOR inhibitor and demonstrated that treatment of OVA-challenged mice with the inhibitor (1 mg/kg i.v.) was effective at reducing airway eosinophil infiltration and methacholine-induced bronchoconstriction (using whole body plesthymography).…”

Section: Discussionmentioning

confidence: 95%

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

et al. 2013

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Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.

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Section: Discussionmentioning

confidence: 95%

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

et al. 2013

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“…GSNOR inhibition increases GSNO availability in the cell and in turn facilitates •NO-mediated signaling pathways. Dozens of small molecules have been identified that can inhibit GSNOR to varying degrees (Green et al, 2012; Jiang et al, 2016; Sanghani et al, 2009; Sun et al, 2012, 2011a, 2011b). Two of these, N6022 (3-(5-(4-(1H-imidazol-1-yl) phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl) propionic acid) and N91115 from Nivalis Pharmaceuticals show promise as potentially safe and effective GSNOR inhibitors that have undergone clinical trial for both the treatment of mild asthma (clinicaltrials.gov - NCT01316315), and cystic fibrosis in individuals who are heterozygous for the cystic fibrosis transmembrane conductance regulator (CFTR) gating mutation CFTRΔF508+ (clinicaltrials.gov – N6022: NCT01746784; N91115: NCT02724527).…”

Section: Therapeutic Inhibition Of Gsnormentioning

confidence: 99%

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

Barnett

Buxton

2017

Critical Reviews in Biochemistry and Molecular Biology

119

101

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S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development, and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, are closely tied to GSNOR regulation and define this enzyme as an important therapeutic target.

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“…The oxidoreductase, S-nitrosoglutathione reductase (GSNOR), is the primary enzyme involved in the catabolism of intracellular GSNO, and its pharmacologic inhibition provides a therapeutic mechanism for preserving intracellular GSNO levels. High potency GSNOR inhibitors are currently under clinical development [4]–[7].…”

Section: Introductionmentioning

confidence: 99%

ADH IB Expression, but Not ADH III, Is Decreased in Human Lung Cancer

Mutka¹,

Green²,

Verderber³

et al. 2012

PLoS ONE

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Endogenous S-nitrosothiols, including S-nitrosoglutathione (GSNO), mediate nitric oxide (NO)-based signaling, inflammatory responses, and smooth muscle function. Reduced GSNO levels have been implicated in several respiratory diseases, and inhibition of GSNO reductase, (GSNOR) the primary enzyme that metabolizes GSNO, represents a novel approach to treating inflammatory lung diseases. Recently, an association between decreased GSNOR expression and human lung cancer risk was proposed in part based on immunohistochemical staining using a polyclonal GSNOR antibody. GSNOR is an isozyme of the alcohol dehydrogenase (ADH) family, and we demonstrate that the antibody used in those studies cross reacts substantially with other ADH proteins and may not be an appropriate reagent. We evaluated human lung cancer tissue arrays using monoclonal antibodies highly specific for human GSNOR with minimal cross reactivity to other ADH proteins. We verified the presence of GSNOR in ≥85% of specimens examined, and extensive analysis of these samples demonstrated no difference in GSNOR protein expression between cancerous and normal lung tissues. Additionally, GSNOR and other ADH mRNA levels were evaluated quantitatively in lung cancer cDNA arrays by qPCR. Consistent with our immunohistochemical findings, GSNOR mRNA levels were not changed in lung cancer tissues, however the expression levels of other ADH genes were decreased. ADH IB mRNA levels were reduced (>10-fold) in 65% of the lung cancer cDNA specimens. We conclude that the previously reported results showed an incorrect association of GSNOR and human lung cancer risk, and a decrease in ADH IB, rather than GSNOR, correlates with human lung cancer.

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Structure–activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: Carboxamide modification

Cited by 16 publications

References 25 publications

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

ADH IB Expression, but Not ADH III, Is Decreased in Human Lung Cancer

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