GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Cellzome GmbH, A GlaxoSmithKline Company, Meyerhofstraße 1, 69117 Heidelberg, Germany.
J Med Chem. 2022 Jan 13;65(1):633-664. doi: 10.1021/acs.jmedchem.1c01765. Epub 2021 Dec 20.
The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.
酪氨酸激酶家族的 Janus（JAK1、JAK2、JAK3 和 TYK2）在细胞因子的受体信号传导中发挥着重要作用，而这些细胞因子与严重哮喘的发病机制有关，因此人们对开发小分子吸入型 JAK 抑制剂作为治疗方法产生了浓厚的兴趣。在这里，我们描述了喹唑啉系列 JAK 抑制剂的优化，以及在小鼠肺部药代动力学（PK）研究中仅观察到母体化合物低浓度的结果。随后的研究表明，低暴露是由于醛氧化酶（AO）代谢所致，因此我们试图寻找不受 AO 代谢的喹唑啉。我们发现，喹唑啉 2 位的特定取代基可以防止 AO 代谢，这可以通过在 AO 结合位点的计算对接研究来合理化，但它们会损害激酶组选择性。这里呈现的结果强调了 AO 代谢是肺部的一个潜在问题。
