Synthesis of Effective and Safe Mucolytics for Pulmonary Disease

描述(申请人提供)：粘液运输是肺的天然防御的基本组成部分。在许多环境和遗传性呼吸道疾病中，异常的粘液运输会导致粘液粘连，从而导致粘液滞留。粘液粘连通过产生气流阻塞、炎症和感染导致“支气管炎”的发病。粘液粘连引起的支气管炎最好的例子可能是急性病毒感染、长时间插管和/或中枢神经系统疾病。在相关的上下文中，与COPD、CF和PCD相关的“急性加重”(AEs)通常反映支气管炎扩散到以前正常的肺部区域。因此，在肺部医学中，一般需要药物清除呼吸道表面的粘液，以缓解症状和减缓/阻止疾病进展。因此，我们的目标是开发一种新的粘液溶解剂，作为单一的或联合水剂使用，以治疗有需要的患者的粘液滞留。基于一种新的“双凝胶”假说来更好地描述粘液纤毛器，已经开发出生物物理公式来描述健康中的粘液流动和疾病中的流动失败。这些配方已经扩展到分析在疾病状态下粘连的粘液的特性，并确定恢复运输的策略。我们已经开发了“咳嗽机器”和其他生物物理测试方法来测量产生粘连的生物物理力，并寻找药物来恢复清除。这一探索导致了对作为关键添加剂/增效剂的二硫键还原剂的关注。吸入型N-乙酰半胱氨酸(NAC)因其固有活性差和在呼吸道表面的半衰期短而在肺部药物治疗中失败。因此，启动了一项化学计划，以确定优质的基于硫醇的支架(例如，包括DTT支架)，并应用相关化学计划的策略来增加基于硫醇的还原剂的活性，并增加它们在呼吸道表面的停留时间。这些方法导致了先导化合物(P2062)的选择，该化合物比其他基于硫醇的粘附剂(~1,000倍)具有更高的活性，在呼吸道表面更持久(更长的T1/2)，并限制细胞渗透，因此比NAC具有安全优势。我们的新型减粘剂可有效减少COPD痰中的MUC5AC和MUC5B，清除ENaC小鼠模型中的粘连粘液，清除原发纤毛运动障碍小鼠犀牛/鼻窦腔中的粘连粘液，并通过气管粘液速度测定恢复中性粒细胞弹性蛋白酶治疗的绵羊的粘液清除。优化P2062和产生临床候选药物的策略在特定目标1的四级方法中概述，该方法侧重于安全性和有效性的提高。具体目标2概述了将临床铅转移到IND所需的过程，包括需要药物化学、毒理学、ADME和PK研究的所有IND。我们预计在学员资助期结束时立即启动第一阶段试验。 (摘要结束)

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)