Sun Xicheng, Wasley Jan W F, Qiu Jian, Blonder Joan P, Stout Adam M, Green Louis S, Strong Sarah A, Colagiovanni Dorothy B, Richards Jane P, Mutka Sarah C, Chun Lawrence, Rosenthal Gary J
N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, Colorado 80301, United States.
Simpharma LLC, 1 Stone Fence Lane, Guilford, Connecticut 06437, United States.
ACS Med Chem Lett. 2011 Mar 11;2(5):402-6. doi: 10.1021/ml200045s. eCollection 2011 May 12.
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.
S-亚硝基谷胱甘肽还原酶（GSNOR）通过分解代谢S-亚硝基谷胱甘肽（GSNO）在体内调节S-亚硝基硫醇（SNOs）和一氧化氮（NO）。GSNOR以及SNOs、GSNO和NO的抗炎和平滑肌舒张活性在肺、心血管和胃肠道功能中发挥重要作用。在GSNOR基因敲除小鼠中，基础气道张力降低，对支气管收缩剂或气道过敏原刺激的反应减弱。因此，GSNOR已成为几种临床上重要的人类疾病的有吸引力的治疗靶点。据此，开发了GSNOR的小分子抑制剂。这些GSNOR抑制剂在以GSNO和生物可利用NO水平降低为特征的炎症性疾病动物模型中具有强效、选择性和有效性。N6022是一种强效且可逆的GSNOR抑制剂，在哮喘小鼠模型中可减轻支气管收缩和肺部炎症，并显示出可接受的安全性。N6022目前正在进行临床开发，作为治疗急性哮喘的潜在药物。
