Aminosterol Compounds as Therapeutic for Asthma

氨基甾醇化合物治疗哮喘

• 批准号: 6444127
• 负责人: ROY C. LEVITT
• 金额: $ 42.23万
• 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 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444127
• 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）：II期研究将强调继续 体外和体内数据收集以鉴定Genaera氨基甾醇文库 用于治疗变应原诱导的呼吸道炎症的化合物， 专注于哮喘。首先使用体外终点定义先导化合物 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， 替代可能的口腔活动。仔细的药代动力学和活性数据 烟曲霉孢子诱导的铅化合物的测量 使用口服和气管内途径的小鼠气道炎症模型 随后将采取氨基甾醇给药， 用于正式的临床前开发。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， 积极参与第一阶段的研究，为intraperitheal交付，而发现一个 口服活性氨基甾醇在平行实验中优先考虑。 制备和配制符合GMP标准的单一氨基甾醇先导化合物， 然后通过首选的路线迅速建立交付， 管理，沿着必要的支持分析方法开发， 将启动第一项急性大鼠毒性GLP研究，作为第一项 一系列临床前安全性研究，以支持在人类中使用。最终 目标是到2004年进入哮喘患者的人体临床试验， 来自II期SBIR研究的口服氨基甾醇。 拟定商业应用： 哮喘影响超过14？1500万美国公民，其中500万是儿童，每年有5,000多人死于哮喘病。据估计，2000年与哮喘有关的健康费用将超过145亿美元，而在内城居民中，哮喘（和哮喘费用）正在上升。对于哮喘的更好和更新颖的治疗方法，特别是那些副作用更少并且更容易为患者使用的治疗方法，存在显著的需求。氨基类固醇是Genaera公司发现的一类新的抗炎剂，其优先对Th 2型T细胞具有活性，并且可以为哮喘患者提供几个优点，包括自我管理的能力。