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Discovery of s-nitrosoglutathione reductase inhibitors: potential agents for the treatment of asthma and other inflammatory diseases.

Abstract：

: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.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Sun X,Wasley JW,Qiu J,Blonder JP,Stout AM,Green LS,Strong SA,Colagiovanni DB,Richards JP,Mutka SC,Chun L,Rosenthal GJ

doi

10.1021/ml200045s

subject

Has Abstract

pub_date

2011-03-11 00:00:00

pages

402-6

issue

5

issn

1948-5875

journal_volume

2

pub_type

杂志文章

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