title: 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.
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Xicheng
authors.initials: X
authors.lastname: Sun
authors.affiliation: Simpharma LLC, 1 Stone Fence Lane, Guilford, Connecticut 06437, United States.
authors.forename: Jan W F
authors.initials: JW
authors.lastname: Wasley
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Qiu
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Joan P
authors.initials: JP
authors.lastname: Blonder
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Stout
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Louis S
authors.initials: LS
authors.lastname: Green
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Strong
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Dorothy B
authors.initials: DB
authors.lastname: Colagiovanni
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Jane P
authors.initials: JP
authors.lastname: Richards
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mutka
authors.affiliation: Emerald BioStructures, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chun
authors.affiliation: N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Rosenthal
keywords: GSNO; GSNOR; N6022; asthma; nitric oxide; pyrrole