N30 Pharmaceuticals LLC, 3122 Sterling Circle, Suite 200, Boulder, CO 80301, USA.
Bioorg Med Chem Lett. 2011 Oct 1;21(19):5849-53. doi: 10.1016/j.bmcl.2011.07.103. Epub 2011 Aug 3.
The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious S-nitrosoglutathione reductase (GSNOR) inhibitor and is currently undergoing clinical development for the treatment of acute asthma. GSNOR is a member of the alcohol dehydrogenase family (ADH) and regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). Reduced levels of GSNO, as well as other nitrosothiols (SNOs), have been implicated in the pathogenesis of many diseases including those of the respiratory, cardiovascular, and gastrointestinal systems. Preservation of endogenous SNOs through GSNOR inhibition presents a novel therapeutic approach with broad applicability. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on removal of cytochrome P450 inhibition activities. We identified potent and novel GSNOR inhibitors having reduced CYP inhibition activities and demonstrated efficacy in a mouse ovalbumin (OVA) model of asthma.
最近发现基于吡咯的 N6022 是一种有效的、选择性的、可逆的 S-亚硝基谷胱甘肽还原酶（GSNOR）抑制剂，目前正在进行治疗急性哮喘的临床开发。GSNOR 是醇脱氢酶家族（ADH）的成员，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 以及其他的亚硝硫醇（SNOs）水平的降低与许多疾病的发病机制有关，包括呼吸系统、心血管系统和胃肠道系统的疾病。通过抑制 GSNOR 来保留内源性 SNOs 提供了一种具有广泛适用性的新型治疗方法。我们在这里描述了新型吡咯基 N6022 类似物的合成和构效关系（SAR），重点是消除细胞色素 P450 抑制活性。我们鉴定出了具有降低 CYP 抑制活性的新型强效 GSNOR 抑制剂，并在小鼠卵清蛋白（OVA）哮喘模型中证明了其疗效。
