Preclinical Development of an Anti-Mucus Drug

项目描述（由申请人提供）：本项目旨在研制一种抗黏液药物，用于治疗呼吸道疾病。在美国和世界范围内，慢性阻塞性肺病和哮喘等气道疾病是导致发病率和死亡率的主要原因，这些疾病的严重形式与阻塞气道的炎性粘液过量产生有关。然而，目前还没有特异性和有效的治疗方法来减少气道粘液的产生。细胞因子IL-13被认为是哮喘和COPD患者气道粘液生成的有效刺激因子，目前正在进行抗IL-13生物制剂的临床试验。我们认为，一种小分子可以减弱IL-13刺激（但不是基线）的粘液产生，这将解决气道疾病治疗的主要需求。此外，针对气道上皮细胞本身的药物可能具有显著的特异性和有效性优势。我们发现了一种新的粘液生成途径，包括il -13诱导氯离子通道钙活化1 (CLCA1)，然后激活丝裂原活化蛋白激酶13 （MAPK13）。这种CLCA1-MAPK13信号通路在实验模型中被定义，但在COPD和可能的哮喘引起的粘液分泌过多的患者中也很活跃。基于结构的药物设计导致了第一种有效的MAPK13抑制剂的开发，这种抑制剂可以安全地减少il -13刺激（但不是基线）人气道上皮细胞中的粘液产生，现在在体外和体内的猪炎症气道粘液产生模型中显示有效。因此，该项目旨在提供一种安全有效的MAPK13抑制剂，用于治疗COPD和相关高分泌疾病中发现的粘液分泌过多。UH2阶段将实现两个目标。Aim 1将优化MAPK13先导抑制剂，以减弱人气道上皮细胞中IL-13刺激的粘液产生，并将确保临床前开发候选药物选择所需的标准化体外ADMET证据。目的2将在大型动物模型中确定IL-13依赖性气道粘液产生的条件，该模型适用于体外和体内测试抗粘液药物。UH3阶段将推进三个目标。目标1将制定口服和吸入的候选化合物，并完成标准化的体内ADMET-PK/PD研究。目的2将继续进行候选药物在大型粘液产生动物模型中的安全性和有效性。目标3将制定候选药物在人体中的使用方案，包括IND状态的安全性、监管和扩大要求。每个Aim都有明确的时间表和基准。总之，我们期望找到一种临床候选的MAPK13抑制剂，作为第一个小分子治疗药物来控制多余的炎性粘液产生。我们的抗粘液药物预计的市场是高分泌疾病，如慢性阻塞性肺病和哮喘。该项目将根据商业计划运作，包括华盛顿大学申请的专有抗粘液化合物专利和最终的人体临床试验，以获得FDA批准MAPK13抑制剂作为抗粘液药物。

DESCRIPTION (provided by applicant): This project is designed to deliver an anti-mucus drug for the treatment of respiratory airway disease. Airway diseases such as COPD and asthma are leading causes of morbidity and mortality in the U.S. and worldwide and serious forms of these diseases are linked to excess production of inflammatory mucus that obstructs the airway. However, there are no specific and effective therapies to attenuate airway mucus production. The cytokine IL-13 is implicated as a potent stimulus of airway mucus production in both asthma and COPD, and there are ongoing clinical trials of anti-IL-13 biologics. We reasoned that a small molecule to attenuate IL-13- stimulated (but not baseline) mucus production would address a major need for therapy of airway disease. Moreover, a drug targeted to airway epithelial cells themselves could offer significant advantages of specificity and efficacy. We discovered a novel pathway for mucus production that includes IL-13-induction of chloride channel calcium activated 1 (CLCA1) and then activation of mitogen activated protein kinase 13 (MAPK13). This CLCA1-MAPK13 signaling pathway was defined in experimental models but is also active in patients with excess mucus production due to COPD and likely asthma as well. Structure-based drug design led to the development of the first potent MAPK13 inhibitors, which safely attenuated IL-13-stimulated (but not baseline) mucus production in human airway epithelial cells and now appear effective in vitro and in vivo in a pig model of inflammatory airway mucus production. This Project therefore aims to deliver a safe and effective MAPK13 inhibitor for the treatment of excess mucus production found in COPD and related hypersecretory conditions. The UH2 Phase will accomplish two aims. Aim 1 will optimize lead MAPK13 inhibitors to attenuate IL-13- stimulated mucus production in human airway epithelial cells and will secure standardized in vitro ADMET evidence required for selection of a preclinical development candidate. Aim 2 will finalize conditions for IL-13- dependent airway mucus production in a large animal model that is suitable for testing anti-mucus drugs in vitro and in vivo. The UH3 Phase will advance three Aims. Aim 1 will formulate oral and inhaled candidate compounds and complete standardized in vivo ADMET-PK/PD studies. Aim 2 will proceed to safety and efficacy of candidate drugs in a large animal model of mucus production. Aim 3 will develop a protocol for use of candidate drug in humans, including safety, regulatory, and scale-up requirements for IND status. Each Aim has a defined timeline and benchmark. Together, we expect to arrive at a clinical candidate for a MAPK13 inhibitor as the first small-molecule therapeutic to control excess inflammatory mucus production. The projected market for our anti-mucus drug is hypersecretory conditions such as COPD and asthma. The Project will operate under a business plan that includes a patent filed by Washington University for proprietary anti-mucus compounds and eventual clinical trials in humans to achieve FDA approval of a MAPK13 inhibitor as an anti-mucus drug. (End of Abstract)