Preclinical Development of an Anti-Mucus Drug

描述(由申请人提供)：该项目旨在提供一种治疗呼吸道疾病的抗粘液药物。在美国和世界各地，COPD和哮喘等呼吸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过度产生炎性粘液有关，从而阻塞呼吸道。然而，目前还没有特效的治疗方法来减少呼吸道粘液的产生。细胞因子IL-13被认为是哮喘和COPD患者呼吸道粘液产生的有力刺激因素，目前正在进行抗IL-13生物制品的临床试验。我们推测，一个小分子来减弱IL-13刺激(但不是基线)的粘液产生将解决呼吸道疾病治疗的主要需求。此外，针对呼吸道上皮细胞本身的药物可以提供显著的特异性和有效性优势。我们发现了一种新的粘液产生途径，包括IL-13诱导氯离子通道钙激活1(CLCA1)，然后激活丝裂原激活蛋白激酶13(MAPK13)。这个CLCA1-MAPK13信号通路是在实验模型中定义的，但在COPD和可能的哮喘引起的粘液分泌过多的患者中也是活跃的。基于结构的药物设计导致了第一个有效的MAPK13抑制剂的开发，它安全地减弱了IL-13刺激的(但不是基线)人呼吸道上皮细胞的粘液产生，现在在体外和体内炎症呼吸道粘液产生的猪模型中似乎是有效的。因此，该项目旨在提供一种安全有效的MAPK13抑制剂，用于治疗慢性阻塞性肺疾病和相关的高分泌性疾病中过量的粘液产生。UH2阶段将实现两个目标。目的1将优化先导MAPK13抑制剂以减少IL-13刺激的人呼吸道上皮细胞黏液产生，并将确保选择临床前开发候选药物所需的标准化体外ADMET证据。目的2将在一个大型动物模型中最终确定依赖IL-13的呼吸道粘液产生的条件，该模型适合于在体外和体内测试抗粘液药物。UH3阶段将推进三个目标。目的1研制口服和吸入候选化合物，并完成体内标准化的ADMET-PK/PD研究。目的2将在粘液产生的大型动物模型中继续研究候选药物的安全性和有效性。AIM 3将制定一项在人类身上使用候选药物的协议，包括IND状态的安全性、监管和扩大要求。每个目标都有一个明确的时间表和基准。总而言之，我们希望达成一种MAPK13抑制剂的临床候选药物，作为第一种控制过量炎症粘液产生的小分子疗法。我们的抗粘液药物的预计市场是高分泌性疾病，如COPD和哮喘。该项目将在一项商业计划下运作，该计划包括华盛顿大学为专有抗粘液化合物申请的专利，以及最终在人体上进行的临床试验，以实现FDA批准MAPK13抑制剂作为抗粘液药物。 (摘要结束)

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)