Synthesis of Effective and Safe Mucolytics for Pulmonary Disease

描述（由申请人提供）：粘液运输是肺先天防御的基本组成部分。在许多环境性和遗传性气道疾病中，异常粘液运输会产生粘液粘连，从而导致粘液潴留。粘液黏附通过产生气流阻塞、炎症和感染驱动“支气管炎”的发病机制。也许粘液粘连驱动型支气管炎的最佳记录包括急性病毒感染、长时间插管和/或中枢神经系统疾病的患者。在相关背景下，与COPD、CF和PCD相关的“急性加重”（ae）通常反映了支气管炎向先前正常肺区域扩散的一个组成部分。因此，在肺部医学中，通常需要清除气道表面粘附粘液的药物，以提供症状缓解和减缓/阻止疾病进展。因此，我们的目标是开发一种新的黏液解药，作为单一药物或与水合剂组合使用，以治疗需要黏液潴留的患者。基于一种新的“双凝胶”假设来更好地描述黏液纤毛装置，生物物理公式已经被开发出来来描述健康时的黏液流动和疾病时的黏液流动失败。这些公式已经扩展到分析黏液在疾病状态下的特性，并确定恢复运输的策略。我们已经开发了“咳嗽机”和其他生物物理分析来测量产生粘连的生物物理力，并寻找恢复清除的药物。这项研究导致了对二硫键还原剂作为关键添加剂/与水合剂协同作用剂的关注。吸入型n -乙酰半胱氨酸（NAC）由于其内在活性差和在气道表面的半衰期短，在肺部医学中一直失败。因此，我们启动了一项化学计划，以确定优质的硫醇基支架（例如，包括DTT支架），并应用相关化学计划的策略来增加硫醇基还原剂的活性，并增加其在气道表面的停留时间。这些方法导致了一种先导化合物（P2062）的选择，它比其他硫醇基黏液解药（~1,000X）的活性大大提高，在气道表面上更持久（更长t1/2），并限制细胞渗透，因此比NAC具有安全性优势。我们的新型还原剂在减少COPD痰液中的MUC5AC和MUC5B，清除ENaC小鼠模型中的黏附粘液，清除原发性纤毛运动障碍小鼠鼻/窦腔中的黏附粘液，以及通过气管黏液速度测定恢复中性粒细胞弹性蛋白酶治疗的绵羊的黏附粘液清除。在Specific Aim 1中概述了优化P2062和产生临床候选药物的四层方法，其重点是提高安全性和有效性。具体目标2概述了将临床先导物转移到IND所需的过程，包括所有需要药物化学、毒理学、ADME和PK研究的IND。我们预计在CADET资助期结束后立即开始I期试验。

DESCRIPTION (provided by applicant): Mucus transport is a fundamental component of the innate defense of the lung. In many environmental and genetic airways diseases, abnormal mucus transport produces mucus adhesion and, hence, retention. Mucus adhesion drives the pathogenesis of "bronchitis" by generating airflow obstruction, inflammation, and infection. Perhaps the best documented examples of mucus adhesion-driven bronchitis include patients with acute viral infections, prolonged intubation, and/or CNS disease. In a related context, "acute exacerbations" (AEs) associated with COPD, CF, and PCD often reflect a component of bronchitic spread to previously normal areas of the lung. Thus, in pulmonary medicine, there is a general need for agents that clear adherent mucus from airways surfaces to provide both symptomatic relief and slow/stop disease progression. Accordingly, our goal is to develop a novel mucolytic to be used as a single agent, or in combination of hydrating agents, to treat mucus retention in patients in need thereof. Based on a novel "two-gel" hypothesis to better describe the mucociliary apparatus, biophysical formulations have been developed to describe mucus flow in health and failure of flow in disease. These formulations have been extended to analyze the properties of mucus that becomes adherent in disease states and identify strategies to restore transport. We have developed "cough machines" and other biophysical assays to measure the biophysical forces that generate adhesion and search for pharmacologic agents to restore clearance. This search led to a focus on disulfide bond reducing agents as key additive/synergistic agents with hydrating agents. Inhaled N-acetylcysteine (NAC) has failed in pulmonary medicine because of the poor intrinsic activity of the compound and short half-life on airway surfaces. Consequently, a chemistry program was initiated to identify superior thiol-based scaffolds (e.g., including DTT scaffolds) and apply strategies from related chemistry programs to increase the activity of thiol-based reducing agents and to increase their residence time on airway surfaces. These approaches led to the selection of a lead compound (P2062) that exhibits greatly increased activity over other thiol-based mucolytics (~1,000X), is more durable (longer t1/2) on airway surfaces, and limits cellular penetration and hence has safety advantages over NAC. Our novel reducing agents are active in reducing both MUC5AC and MUC5B in COPD sputum, clearing adherent mucus from the �ENaC mouse model, clearing adherent mucus from the rhino/sinus cavity from primary ciliary dyskinesia mice, and restoring mucus clearance in neutrophil elastase treated sheep by the tracheal mucus velocity assay. Strategies to optimize P2062 and generate a clinical candidate are outlined in a four tier approach in Specific Aim 1, which focuses on both increases in safety and efficacy. Processes required to move the clinical lead to an IND are outlined in Specific Aim 2, including all of the IND requiring medicinal chemistry, toxicology, ADME, and PK studies. We anticipate immediate initiation of Phase I trials at the end of the CADET funding period.