J Med Chem. 2019 Oct 24;62(20):9045-9060. doi: 10.1021/acs.jmedchem.9b00533. Epub 2019 Oct 14.
Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone , a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
Janus 激酶（JAK）在调节与哮喘和慢性阻塞性肺疾病相关的炎症细胞因子的表达和功能方面发挥着关键作用。本文描述了一系列新型嘌呤酮 JAK 抑制剂的设计、合成和药理学评价，这些抑制剂具有适合吸入给药的特征。用吡啶酮环取代该系列最初化合物中存在的咪唑并吡啶铰链结合基序，可减轻细胞毒性。进一步受结构生物学研究驱动的系统结构-活性关系（SAR）研究导致发现了吡啶酮，这是一种有效的泛 JAK 抑制剂，具有良好的选择性、长肺部滞留时间、低口服生物利用度，并通过吸入途径在脂多糖诱导的大鼠气道炎症模型中证明了疗效。
