Human 15-lipoxygenase-1 (h-15-LOX-1) is a mammalian lipoxygenase and plays an important role in several inflammatory lung diseases such as asthma, COPD, and chronic bronchitis. Novel potent inhibitors of h-15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery efforts. In this study, we applied an approach in which we screened a fragment collection that is focused on a diverse substitution pattern of nitrogen-containing heterocycles such as indoles, quinolones, pyrazoles, and others. We denoted this approach substitution-oriented fragment screening (SOS) because it focuses on the identification of novel substitution patterns rather than on novel scaffolds. This approach enabled the identification of hits with good potency and clear structure–activity relationships (SAR) for h-1-5-LOX-1 inhibition. Molecular modeling enabled the rationalization of the observed SAR and supported structure-based design for further optimization to obtain inhibitor 14d that binds with a K_i of 36 nM to the enzyme. In vitro and ex vivo biological evaluations of our best inhibitor demonstrate a significant increase of interleukin-10 (IL-10) gene expression, which indicates its anti-inflammatory properties.

中文翻译：

---

具有体外和离体抗炎特性的强效 15-脂氧合酶 1 抑制剂的合理开发

人 15-脂氧合酶-1 (h-15-LOX-1) 是哺乳动物的脂氧合酶，在哮喘、慢性阻塞性肺病和慢性支气管炎等多种炎症性肺病中起重要作用。需要新的强效 h-15-LOX-1 抑制剂来进一步探索这种酶的作用并进行药物发现工作。在这项研究中，我们采用了一种方法，我们筛选了一个片段集合，该片段集合专注于含氮杂环的多样化取代模式，如吲哚、喹诺酮类、吡唑类等。我们将这种方法称为面向替代的片段筛选 (SOS)，因为它侧重于识别新的替代模式而不是新的支架。这种方法能够识别对 h-1-5-LOX-1 抑制具有良好效力和清晰结构-活性关系 (SAR) 的命中。14d以 36 nM的K _i与酶结合。我们最好的抑制剂的体外和离体生物学评估表明白细胞介素 10 (IL-10) 基因表达显着增加，这表明其具有抗炎特性。