Preclinical Development of an Anti-Mucus Drug

描述（由申请人提供）：本项目旨在提供一种用于治疗呼吸道疾病的抗粘液药物。气道疾病如COPD和哮喘是美国和世界范围内发病率和死亡率的主要原因，并且这些疾病的严重形式与阻塞气道的炎性粘液的过量产生有关。然而，没有特异性和有效的疗法来减弱气道粘液的产生。细胞因子IL-13被认为是哮喘和COPD中气道粘液产生的有效刺激物，并且抗IL-13生物制剂的临床试验正在进行中。我们推断，减弱IL-13刺激的（但不是基线）粘液产生的小分子将解决气道疾病治疗的主要需求。此外，靶向气道上皮细胞本身的药物可以提供特异性和有效性的显着优势。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（CLCA 1），然后激活丝裂原激活蛋白激酶13（MAPK 13）。这种CLCA 1-MAPK 13信号通路在实验模型中被定义，但在由于COPD和可能的哮喘而产生过量粘液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MAPK 13抑制剂的开发，其安全地减弱了IL-13刺激的（但不是基线）人类气道上皮细胞中的粘液产生，并且现在在体外和体内炎症气道粘液产生的猪模型中显示出有效性。因此，该项目旨在提供一种安全有效的MAPK 13抑制剂，用于治疗COPD和相关分泌过多病症中发现的粘液过量产生。UH 2阶段将实现两个目标。目标1将优化先导MAPK 13抑制剂以减弱人气道上皮细胞中IL-13刺激的粘液产生，并将确保选择临床前开发候选物所需的标准化体外ADMET证据。目标2将最终确定IL-13依赖性气道粘液产生的条件，在一个大的动物模型，适用于测试抗粘液药物在体外和体内。UH 3阶段将推进三个目标。目的1将制定口服和吸入候选化合物，并完成标准化的体内ADMET-PK/PD研究。目标2将继续研究候选药物在粘液产生的大型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类中使用的方案，包括IND状态的安全性，监管和规模扩大要求。每个目标都有一个明确的时间轴和基准。总之，我们希望能找到一种MAPK 13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治疗药物。我们的抗粘液药物的预期市场是高分泌疾病，如COPD和哮喘。该项目将根据一项商业计划运作，其中包括华盛顿大学提交的专利抗粘液化合物和最终的人体临床试验，以获得FDA批准的MAPK 13抑制剂作为抗粘液药物。 (End摘要）

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)