N30 Papers
- February 15, 2012
Mechanism of Inhibition for N6022, a First-in-Class Drug Targeting S-Nitrosoglutathione Reductase
Louis S. Green, Lawrence E. Chun, Aaron K. Patton, Xicheng Sun, Gary J. Rosenthal, and Jane P. Richards
N6022 is a novel, first-in-class drug with potent inhibitory activity against S-nitrosoglutathione reductase (GSNOR), an enzyme important in the metabolism of S-nitrosoglutathione (GSNO) and in the maintenance of nitric oxide (NO) homeostasis.
Inhibition of GSNOR by N6022 and related compounds has shown safety and efficacy in animal models of asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease [Sun, X., et al. (2011) ACS Med. Chem. Lett. 2, 402–406]. N6022 is currently in early phase clinical studies in humans.
Biochemistry, 2012, 51 (10), pp 2157–2168, DOI: 10.1021/bi201785u, Publication Date (Web): February 15, 2012 (More…Pubs ACS website)
- January 13, 2012
Structure–activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: Carboxamide modification
Xicheng Sun, Jian Qiu, Sarah A. Strong, Louis S. Green, Jan W.F. Wasley, Joan P. Blonder, Dorothy B. Colagiovannia, Adam M. Stout, Sarah C. Mutka, Jane P. Richards, Gary J. Rosenthal
The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems.
The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure–activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety.
Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 6, 15 March 2012, Pages 2338–2342 (More…Science Direct website)
- July 26, 2011
Discovery of potent and novel S-nitrosoglutathione reductase inhibitors devoid of cytochrome P450 activities
Xicheng Sun, Jian Qiu, Sarah A. Strong, Louis S. Green, Jan W.F. Wasley, Joan P. Blonder, Dorothy B. Colagiovannia, Adam M. Stout, Sarah C. Mutka, Jane P. Richards, Gary J. Rosenthal
The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious S-nitrosoglutathione reductase (GSNOR) inhibitor and is currently undergoing clinical development for the treatment of acute asthma. GSNOR is a member of the alcohol dehydrogenase family (ADH) and regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). Reduced levels of GSNO, as well as other nitrosothiols (SNOs), have been implicated in the pathogenesis of many diseases including those of the respiratory, cardiovascular, and gastrointestinal systems. Preservation of endogenous SNOs through GSNOR inhibition presents a novel therapeutic approach with broad applicability.
We describe here the synthesis and structure–activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on removal of cytochrome P450 inhibition activities. We identified potent and novel GSNOR inhibitors having reduced CYP inhibition activities and demonstrated efficacy in a mouse ovalbumin (OVA) model of asthma.
Bioorganic & Medicinal Chemistry Letters, Volume 21, Issue 19, 1 October 2011, Pages 5849–5853 (More…Science Direct website)
- April 19, 2011
Structure–activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: Pyrrole regioisomers and propionic acid replacement
Xicheng Sun, Jian Qiu, Sarah A. Strong, Louis S. Green, Jan W.F. Wasley, Joan P. Blonder, Dorothy B. Colagiovanni, Sarah C. Mutka, Adam M. Stout, Jane P. Richards, Lawrence Chun, Gary J. Rosenthal
S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development.
We describe here the synthesis and structure–activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.
Bioorganic & Medicinal Chemistry Letters 21 (2011) 3671–3675. (More…Science Direct website)
- March 11, 2011
Discovery of S-Nitrosoglutathione Reductase Inhibitors: Potential Agents for the Treatment of Asthma and Other Inflammatory Diseases
Xicheng Sun, Jan W. F. Wasley, Jian Qiu, Joan P. Blonder, Adam M. Stout, Louis S. Green, Sarah A. Strong, Dorothy B. Colagiovanni, Jane P. Richards, Sarah C. Mutka, Lawrence Chun, and Gary J. Rosenthal
S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal function. In GSNOR knockout mice, basal airway tone is reduced and the response to challenge with bronchoconstrictors or airway allergens is attenuated. Consequently, GSNOR has emerged as an attractive therapeutic target for several clinically important human diseases. As such, small molecule inhibitors of GSNOR were developed.
These GSNOR inhibitors were potent, selective, and efficacious in animal models of inflammatory disease characterized by reduced levels of GSNO and bioavailable NO. N6022, a potent and reversible GSNOR inhibitor, reduced bronchoconstriction and pulmonary inflammation in a mouse model of asthma and demonstrated an acceptable safety profile.
N6022 is currently in clinical development as a potential agent for the treatment of acute asthma.
ACS Med. Chem. Lett. 2011, 2, 402–406. (More…Pubs ACS website)
- August 25, 2011
Preclinical 28-Day Inhalation Toxicity Assessment of S-Nitrosoglutathione
Dorothy B. Colagiovanni, Daxa Borkhataria, Doug Looker, Detlef Schuler, Corinna Bachmann, Peter Sagelsdorff, Naveed Honarvar, and Gary J. Rosenthal
To support clinical development of S-nitrosoglutathione (GSNO) as a therapeutic agent, 28-day toxicology studies in rats and dogs were conducted. Rats (21-25/sex) and dogs (3-5/sex) were exposed for 4 hours or 1 hour, respectively, to inhaled GSNO (0, 3, 9.3, 19, and 28 mg/kg per d in rats and 0, 4.6, 9.0, and 16.2 mg/kg per d in dogs) or vehicle daily via a nebulizer. Animals were monitored throughout the 28-day dosing period and during a postexposure recovery period.
Complete necropsy and tissue examinations were performed. Experimental end points included clinical pathology, toxicokinetics, and immunotoxicology. No biologically significant adverse findings were noted in either species, and the no observed adverse effect levels (NOAELs) under these conditions were the highest achieved doses (28 and 16.2 mg/kg per d in rats and dogs, respectively). These data demonstrate that GSNO is well tolerated in rodents and dogs and predict a favorable toxicity profile in humans, thus supporting future clinical development of GSNO or closely related compounds.
International Journal of Toxicology October 2011 vol. 30 no. 5 466-477 (More…Sage Journals website)
- December 28, 2012
ADH IB Expression, but Not ADH III, Is Decreased in Human Lung Cancer
Sarah C. Mutka, Lucia H. Green, Evie L. Verderber, Jane P. Richards, Doug L. Looker, Elizabeth A. Chlipala, Gary J. Rosenthal
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.
(2012) PLoS ONE 7(12): e52995. doi:10.1371/journal.pone.0052995 (More…PLOS ONE website)
- January 24, 2013
Pharmacological Inhibition of S-Nitrosoglutathione Reductase Improves Endothelial Vasodilatory Function in Rats in vivo
Qiumei Chen, Richard E. Sievers, Monika Varga, Sourabh Kharait, Daniel J. Haddad, Aaron K. Patton, Christopher S. Delany, Sarah C. Mutka, Joan P. Blonder, Gregory P. Dubé, Gary J. Rosenthal, and Matthew L. Springer
Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short-lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown.
To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single i.v. dose of N6338 preserved FMD (15.3±5.4% vs. 14.2±6.3%, P=NS) under partial NOS inhibition that normally reduces FMD by roughly 50% (14.1±2.9% vs.7.6±4.4%, P<0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0±5.3/122.7±6.4 mmHg vs. 203.8±1.9/143.7±7.5 mmHg for vehicle, P<0.001) and vascular resistance index (1.5±0.4 mmHg·min/L vs. 3.2±1.0 mmHg·min/L for vehicle, P<0.001), and restored FMD from an initially impaired state (7.4±1.7% day 0) to a level (13.0±3.1% day 14, P<0.001) similar to that observed in normotensive rats.
N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension.
(2013) Journal of Applied Physiology : doi:10.1152/japplphysiol.01302.2012 (More…JAP website – subscription required)