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。在许多环境和遗传性气道疾病中，异常的粘液运输产生粘液粘附，因此，滞留。粘液粘连通过产生气流阻塞、炎症和感染驱动“支气管炎”的发病机制。粘液粘连驱动的支气管炎的最佳病例可能包括急性病毒感染、长时间插管和/或CNS疾病患者。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扩散到先前正常的肺区域的成分。因此，在肺部医学中，普遍需要从气道表面清除粘附粘液以提供症状缓解和减缓/停止疾病进展的试剂。因此，我们的目标是开发一种新的粘液溶解剂，其用作单一药剂或与水合剂组合使用，以治疗有需要的患者的粘液潴留。基于一种新的“双凝胶”假说，以更好地描述粘液纤毛装置，生物物理制剂已被开发来描述粘液流动在健康和故障的流动在疾病。这些配方已被扩展到分析粘液的性质，成为粘附在疾病状态，并确定策略，以恢复运输。我们已经开发了“咳嗽机”和其他生物物理测定来测量产生粘附的生物物理力，并寻找药物来恢复清除。该研究导致关注二硫键还原剂作为与水合剂的关键添加剂/协同剂。吸入N-乙酰半胱氨酸（NAC）在肺部药物中失败，因为该化合物的内在活性差，在气道表面的半衰期短。因此，启动化学程序以鉴定上级硫醇基支架（例如，包括DTT支架），并应用相关化学项目的策略来增加硫醇基还原剂的活性并增加它们在气道表面上的停留时间。这些方法导致选择了先导化合物（P2062），其表现出比其他基于硫醇的粘液溶解剂（~1，000 X）大大增加的活性，在气道表面上更持久（更长的t1/2），并且限制细胞渗透，因此具有比NAC更安全的优势。我们的新型还原剂在减少COPD痰液中的MUC 5AC和MUC 5 B、清除来自ENaC小鼠模型的粘附粘液、清除来自原发性纤毛运动障碍小鼠的鼻/窦腔的粘附粘液以及通过气管粘液速度测定恢复中性粒细胞弹性蛋白酶处理的绵羊中的粘液清除方面具有活性。优化P2062和产生临床候选药物的策略在具体目标1的四层方法中概述，该方法侧重于安全性和有效性的提高。将临床电极导线转移至IND所需的过程概述于具体目标2中，包括需要药物化学、毒理学、ADME和PK研究的所有IND。我们预计在CADET资助期结束时立即启动I期试验。 (END（见摘要）

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. (END OF ABSTRACT)