Aminosterol Compounds as Therapeutic for Asthma

氨基甾醇化合物治疗哮喘

• 批准号: 6622248
• 负责人: ROY C. LEVITT
• 金额: $ 15.3万
• 依托单位: GENAERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622248
• 关键词: asthma; bronchodilators; cholestane compound; drug administration routes; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; laboratory rat; lymphocyte; respiratory disorder chemotherapy; respiratory hypersensitivity; tissue /cell culture

DESCRIPTION (provided by applicant):Phase II research will emphasize continuing in vitro and in vivo data collection to identify Genaera aminosterol library compounds useful in treating atergen-induced respiratory inflammation, with a focus on asthma. Lead compounds will first be defined using in vitro endpoints for interference with lymphocyte function, emphasizing the additional collection of trans-epithelial monolayer barrier penetration data as a surrogate for possible oral activity. Careful pharmacokinetic and activity data measurements for lead compounds in an Aspergillus fumigatus spore-induced murine model of airway inflammation using both oral and intratracheal routes of aminosterol administration will subsequently be taken to select a few aminosterols for formal preclinical development. These compounds will be compared to the water soluble lead compounds MSI-1 432 and MSI-f 828 shown active in phase I research for intratracheal delivery, while discovery of an orally active aminosterol is given priority in parallel experimentation. Preparation and formulation of a single lead aminosterol to GMP standards will then be rapidly instituted for delivery by the preferred route of administration, along with necessary supporting analytical method development, and a first acute rat toxicity GLP study will be initiated as the first of a series of preclinical safety studies to support use in humans. The eventual goal is to enter human clinical trials in asthma patients by 2004 with an orally delivered aminosterol emerging from the phase Il SBIR research. PROPOSED COMMERCIAL APPLICATION: Asthma affects more than 14?15 million U.S. citizens" 5 million of whom are children, and more than 5,000 die of asthmatic disease each year. The health related costs of asthma are estimated for the year 2000 to exceed $14.5 billion, and asthma (and asthma costs) are on the rise among inner city residents. There is a significant need for better and more novel treatments for asthma, notably those with fewer side effects and that are easier for patients to use. Aminosterols are a new class of anti-inflammatory agents discovered by Genaera Corporation that are preferentially active with Th2-type T cells and that may offer several advantages to asthma patients, including the ability to self-administer.

描述（由申请人提供）：第二阶段研究将强调持续 收集体外和体内数据以鉴定 Genaera 氨基甾醇库 可用于治疗过敏原诱发的呼吸道炎症的化合物，具有 关注哮喘。先导化合物将首先使用体外终点来定义 对于干扰淋巴细胞功能，强调额外的 收集跨上皮单层屏障渗透数据作为 替代可能的口头活动。仔细的药代动力学和活性数据 烟曲霉孢子诱导的先导化合物的测量 使用口服和气管内途径的气道炎症小鼠模型 随后将选择一些人服用氨基甾醇 用于正式临床前开发的氨基甾醇。这些化合物将 与所示的水溶性先导化合物 MSI-1 432 和 MSI-f 828 相比 积极开展气管内递送的 I 期研究，同时发现了一种 并行实验中优先考虑口服活性氨基甾醇。 符合 GMP 标准的单一氨基甾醇铅的制备和配方将 然后迅速开始按首选路线进行交付 管理以及必要的支持分析方法开发， 第一项急性大鼠毒性 GLP 研究将作为第一项 一系列临床前安全性研究以支持在人类中的使用。最终的 目标是到 2004 年进入哮喘患者的人体临床试验 II 期 SBIR 研究中出现的口服氨基甾醇。 拟议的商业应用： 哮喘影响着超过 14-1500 万美国公民，其中 500 万是儿童，每年有超过 5,000 人死于哮喘病。估计 2000 年与哮喘有关的健康费用将超过 145 亿美元，而哮喘（和内城区居民的哮喘治疗费用正在上升，因此迫切需要更好、更新颖的哮喘治疗方法，特别是副作用更少且更易于患者使用的治疗方法。氨基甾醇是 Genaera 公司发现的一类新型抗炎剂，它优先对 Th2 型 T 细胞起作用，可能为哮喘患者提供多种优势，包括自我给药的能力。