N30 Pharmaceuticals LLC, 3122 Sterling Circle, Boulder, CO 80301, USA.
Bioorg Med Chem Lett. 2012 Mar 15;22(6):2338-42. doi: 10.1016/j.bmcl.2012.01.047. Epub 2012 Feb 2.
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. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.
酶 S-亚硝基谷胱甘肽还原酶（GSNOR）是醇脱氢酶家族（ADH）的一员，通过分解 S-亚硝基谷胱甘肽（GSNO）来调节 S-亚硝基硫醇（SNOs）的水平。GSNO 和 SNOs 与许多疾病的发病机制有关，包括呼吸系统、胃肠道和心血管系统的疾病。最近，基于吡咯的 N6022 被鉴定为一种有效的、选择性的、可逆的和有效的 GSNOR 抑制剂，目前正在临床开发用于治疗急性哮喘。我们在这里描述了基于吡咯的 N6022 的新型类似物的合成和构效关系（SAR），重点是在侧链 N-苯基部分上进行羧酰胺修饰。我们已经鉴定出具有效力的新型 GSNOR 抑制剂，在卵清蛋白（OVA）诱导的哮喘小鼠模型中显示出疗效。
