N30 Posters and Presentations
- November 11, 2011
S-Nitrosoglutathione Reductase Inhibitors for the Prevention and Treatment of Experimental Colitis
Joan P Blonder, Sarah C Mutka, Xicheng Sun, Daniel W Drolet, Dorothy Colagiovanni, Gregory D Lyng, Charles Scoggin, Gary J Rosenthal
S-nitrosoglutathione reductase (GSNOR) is a Class III alcohol dehydrogenase (ADH) that represents a novel therapeutic target in inflammatory bowel disease (IBD). GSNOR may contribute to IBD through dysregulated activity and thus altered metabolism of its substrate, S-nitrosoglutathione (GSNO), an abundant low molecular weight S-nitrosothiol (SNO).
GSNO serves as a reservoir for nitric oxide (NO), exerts potent anti-inflammatory actions, and maintains epithelial barrier functions in the gut. These studies determined the efficacy of small molecule inhibitors of GSNOR (N6022 and N6547; Table 1) in mouse models of dextran sulfate sodium (DSS) colitis. More…poster PDF(787Kb)
- August 28, 2011
Structure – Activity Relationships of Pyrrole Based S-Nitrosoglutathione Reductase Inhibitors – Carboxamide Modification
Xicheng Sun, Jian Qiu, Sarah A. Strong, Louis S. Green, Jan W. F. Wasley, Dorothy B. Colagiovanni,
Sarah C. Mutka, Joan P. Blonder, Adam M. Stout, Jane P. Richards, Lawrence Chun, and Gary J. RosenthalThe 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, cardiovascular, and gastrointestinal 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 analogues of N6022 focusing on carboxamide modifications.
We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice. More…poster PDF(182Kb)
- July 14, 2011
Heterozygous Deletion of S-Nitrosoglutathione Reductase in Mice Does Not Increase Nitrosative Inactivation of O6-Alkylguanine-DNA Alkyltransferase or Diethylnitrosamine-induced Hepatocarcinogenesis
Dorothy Colagiovanni, Wei Wei, Joan Blonder, Limin Liu, and Gary J. Rosenthal
S-nitrosoglutathione reductase (GSNOR) is the primary enzyme responsible for the metabolism of S-nitrosoglutathione (GSNO).
Through this denitrosylation process, GSNOR plays a central role in regulating the levels of endogenous S-nitrosothiols and protein S-nitrosylation-based signalling. Recent evidence suggests that modulation of proteins via S-nitrosylation may alter DNA repair mechanisms.
For example, the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) can be inactivated through S-nitrosylation of the Cys in the active site of AGT. AGT corrects O6-alkylguanines and thus prevents the mispairing of cytotoxic O6-alkylguanines to thymine by DNA polymerases during DNA replication.
Mice deficient in AGT have been shown to be more susceptible to hepatocarcinogenesis induced by dimethylnitrosamine. More…poster PDF(184Kb)
- May 3, 2011
Oral S-Nitrosoglutathione Reductase Inhibitors Attenuate Pulmonary Inflammation and Decrease Airspace Enlargement in Experimental Models of COPD
Joan P. Blonder, Sarah C. Mutka, Dan Drolet, Bassam Damaj, Dianne Spicer, Vince Russell, Xicheng Sun, Gary J. Rosenthal, Charles Scoggin
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease often associated with cigarette smoking and characterized by progressive airflow limitation and lung damage.
In the lung, endogenous S-nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) mediate nitric oxide (NO)-based signaling, inflammatory status, and smooth muscle function. S-nitrosoglutathione reductase (GSNOR) inhibition represents a novel approach to treating COPD via restoring GSNO and GSNO-mediated anti-inflammatory and bronchodilatory activities.
The efficacy of small molecule inhibitors of GSNOR was evaluated in two murine models of COPD, a porcine pancreatic elastase (PPE) instillation model and a sub-chronic tobacco smoke (TS) inhalation model. More…poster PDF(440Kb)
- March 27, 2011
Discovery of S-nitrosoglutathione reductase inhibitors as potential agents to treat asthma, COPD and IBD
Xicheng Sun, PhD
Boulder, Colo, March 27, 2011 -N30 Pharmaceuticals, LLC (N30 Pharma) today announced that it would make a presentation at the ACS Spring 2011 National Meeting & Exposition in Anaheim, CA starting the week of March 27, 2011. More…presentation PDF(2.5Mb)
- March 8, 2011
Inhibition of the Enzyme S-Nitrosoglutathione (GSNO) Reductase Does Not Cause Mechanism-based Toxicity
D.B. Colagiovanni, X. Sun, J. Qiu, A. Stout, J. Richards, A. Patton, L. Green and G.J. Rosenthal
S-nitrosoglutathione (GSNO) is an endogenous nitrosothiol that serves as both a donor and depot for nitric oxide (NO). The enzyme GSNO reductase (GSNOR), also known as alcohol dehydrogenase Class III (ADH III) or formaldehyde dehydrogenase, catalyzes the metabolism of GSNO and controls levels of intracellular S-nitrosothiols.
Given its central role in controlling NO stores and formaldehyde levels, it is important to understand potential negative consequences of modulating GSNOR. Fortunately, other enzymes are capable of catalyzing the breakdown of formaldehyde, including ADH 1A1 and 2. Based on studies using exogenous NO donors, NO-mediated effects from reduced breakdown could include hypotension, methemoglobinemia and changes in platelet aggregation.
We evaluated potential deleterious effects of GSNOR inhibition using small molecule inhibitors, agents being developed for treatment of respiratory diseases. More…PDF (250Kb)
- September 1, 2010
Discovery of S-nitrosoglutathione reductase (GSNOR) inhibitors as potential agents to treat asthma and related diseases
Xicheng Sun, Jan Wasley, Jian Qiu, Adam Stout, Louis Green, Sarah Strong, Dorothy Colagiovanni, Joan Blonder, Jane Richards, Sarah Mutka and Gary Rosenthal
Increases in bio‐available nitric oxide (NO) are associated with anti‐inflammatory and smooth muscle relaxant effects, especially in organ systems characterized by smooth muscle and endothelial/epithelial layers such as the lung and the cardiovascular system.
S-nitrosoglutathione reductase (GSNOR), a member of the alcohol dehydrogenase family (ADH5), has recently been discovered to regulate intracellular S‐nitrosothiols (SNOs), a biologically important class of stable NO adducts, by reducing S-nitrosoglutathione (GSNO). GSNO is a major NO metabolite derived from the reaction of glutathione with reactive nitrogen species.
GSNO has been shown to elicit many if not all of the biological functions of NO and also serves as a durable depot for NO which has a short biological half life. More…PDF (770Kb)