Design and synthesis of Leukotriene A4 hydrolase inhibitors to alleviate idiopathic pulmonary fibrosis and acute lung injury

• Published in: European journal of medicinal chemistry 2020-10, Vol.203 (C), p.112614-112614, Article 112614
• Main Authors: Li, Xiaohe, Xie, Maodun, Lu, Cheng, Mao, Jiahe, Cao, Yuting, Yang, Yuyu, Wei, Yujiao, Liu, Xinhua, Cao, Sheng, Song, Yang, Peng, Junya, Zhou, Yunyun, Jiang, Qiuyan, Lin, Gang, Qin, Shuanglin, Qi, Min, Hou, Min, Liu, Xiang, Zhou, Honggang, Yang, Guang, Yang, Cheng
• Format: Article
• Language: English
• Subjects: Acute lung injury; Acute Lung Injury - drug therapy; Acute Lung Injury - metabolism; Animals; Chemistry Techniques, Synthetic; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Epoxide Hydrolases - antagonists & inhibitors; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Idiopathic pulmonary fibrosis; Idiopathic Pulmonary Fibrosis - drug therapy; Leukotriene A4 hydrolase; Leukotriene B4 - biosynthesis; Mice; Selective inhibitor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112614

Idiopathic pulmonary fibrosis (IPF) and acute lung injury (ALI) are considered two severe public health issues, attributed to malfunctions of neutrophils. They can cause chronic inflammation and have association with subsequent tissue damages. There have been rare drugs applying to the efficient treatment in clinical practice. Existing research revealed that Leukotriene B4 (LTB4) is the critical endogenous molecule to induce neutrophil inflammatory response. LTB4 blocking biosynthesis is the potential strategy treating IPF and ALI. In the present study, 45 hydroxamic acid derivatives were produced, and compound 26 was screened out as a highly selective Lead compound of Leukotriene A4 Hydrolase (LTA4H), i.e., an enzyme critical to the biosynthesis of LTB4. This compound is capable of relieving neutrophilic inflammation in an IPF mouse model at early stage, as well as mitigating LPS-induced acute lung injury via a mechanism of LTB4 blocking biosynthesis in vivo. Whether this compound acts as the potential lead compound for the treatment of IPF and ALI requires further verification. [Display omitted] •Compound 26 is a highly selective inhibitor of LTA4H.•IC50 of Hydrolase is 99 nM, 2000 fold stronger than IC50 of Aminopeptidase.•Remarkably alleviates IPF & ALI in vivo.