Discovery of New Anti-Inflammatory Agents to Treat COPD

肺气肿慢性阻塞性肺疾病(COPD)是一种日益增多的不可逆转的肺部疾病。 没有有效的疾病修正疗法的流行率。慢性阻塞性肺疾病患者的表现 失调和夸大的炎症和免疫反应。最近的研究表明， 白三烯A4水解酶(LTA4H)的氨基肽酶活性可能在这一过程中起着关键作用 消炎的作用。我们已经独立地证明了对小鼠肺的有效保护 选择性小分子4MDM选择性增强慢性阻塞性肺疾病LTA4H氨基肽酶活性 LTA4H氨基肽酶活性激活剂。当香烟烟雾引起慢性阻塞性肺疾病时，用 4MDM显著减轻死前生理和死后确定的COPD的严重程度 解剖学评估。基于这些发现，我们认为4MDM可以作为一种先导分子用于 发现治疗慢性阻塞性肺疾病的新型抗炎药。因此，我们提出了具体的目标，以更好地 了解靶LTA4H酶结构，发现新的LTA4H氨基肽酶活性激活剂， 并确定这些化合物在COPD发病机制中的作用。我们相信我们的提议 这项工作和预期结果将为治疗COPD患者提供潜在的一流药物。

Emphysematous chronic obstructive pulmonary disease (COPD) is an irreversible lung disease of increasing prevalence for which effective disease modifying therapy is not available. Patients with COPD exhibit dysregulated and exaggerated inflammatory and immunologic responses. Recent studies have shown that the aminopeptidase activity of the leukotriene A4 hydrolase (LTA4H) enzyme may play crucial roles in the process of resolving inflammation. We have independently demonstrated effective protection of murine lungs against COPD by selectively augmenting the LTA4H aminopeptidase activity with 4MDM, a selective small molecule activator of the LTA4H aminopeptidase activity. When COPD was induced with cigarette smoke, treatment with 4MDM significantly reduced severity of COPD as determined by pre-mortem physiologic and post-mortem anatomic assessment. On the basis of these findings, we believe that 4MDM can serve as a lead molecule for the discovery of novel anti-inflammatory agents to treat COPD. Therefore, we propose specific aims to better understand the target LTA4H enzyme structure, discover new activators of the LTA4H aminopeptidase activity, and determine the effect of these compounds in the pathogenesis of COPD. We believe that our proposed work and expected outcomes will provide potential first-in-class drugs to treat patients with COPD.